JP2021507944A - Compositions and treatments for neuropathy, including motor neuron disease - Google Patents

Abstract

The present invention relates to, in at least some aspects, the molecules of the invention, compositions containing them and methods of their use for the treatment of neuropathy. [Selection diagram] Fig. 1

Description

The present invention relates to compositions and therapeutic methods for neuropathy, in particular, compositions containing the molecules of the invention described herein and therapeutic methods using them, in at least some embodiments.

Amyotrophic lateral sclerosis (ALS) is a rare neurological disorder that belongs to a broad group of neurological disorders called motor neuron disease (MND). Amyotrophic lateral sclerosis mainly affects nerve cells (neurons) involved in the control of voluntary muscle movement. The disease is progressive. Currently, there is no cure for ALS and there is no effective treatment to stop or ameliorate the progression of the disease. Two existing ALS drugs, riluzole and edaravone, have been shown to extend patient life by a few months.

ALS belongs to a broad group of diseases known as motor neuron diseases, which are caused by the gradual deterioration (degeneration) and death of motor neurons. Motor neurons are nerve cells that extend from the brain to the spinal cord and to the muscles of the entire body. These motor neurons initiate and provide important communication links between the brain and voluntary muscles.

Messages from motor neurons in the brain (called upper motor neurons) to the spinal cord motor neurons and brain motor neurons (called lower motor neurons), and from the spinal cord and brain motor neurons to specific muscles (s) Is transmitted.

In ALS, both upper and lower motor neurons degenerate or die, stopping the transmission of messages to muscle. When it becomes incapacitated, the muscles gradually weaken, begin to cramp (called fasciculation), and lose weight (atrophy). Eventually, the brain loses the ability to initiate and control voluntary movements.

Background techniques do not provide a treatment that successfully treats ALS (Amyotrophic Lateral Sclerosis). The present invention provides, in at least some embodiments, a composition comprising the molecules of the invention described herein and a therapeutic method using the same. "Molecules of the invention" means molecules that have been shown to have at least one effect in vitro and / or in vivo, as described herein, which is described herein. It has been shown to be useful in the compositions and therapeutic methods of.

Preferably, the treatment involves an increase in energy metabolism in the nervous system.

Optionally, treatment includes one or more of cure, management, amelioration, attenuation, alleviation, minimization, suppression, management or termination of the adverse effects of the disease.

Treatment as Prevention of the Onset of Disease and / or Symptoms According to at least some embodiments, treatment is also determined, for example, by the measurement of optionally one or more diagnostic markers, the symptoms and / or of the disease. It involves at least reducing the onset rate of etiology. Such diagnostic markers are selected according to the particular neuropathy.

It is not desired to be limited to a single hypothesis with respect to the molecules of the invention described herein, but for each disease described herein, the disease in the subject is detected prior to the presentation of complete onset or symptoms. Complete onset of the disease in subjects with no symptoms of these diseases or with only mild initial symptoms by administering to the subject the molecules of the invention described herein according to the administration regimen that is then preferred. Or even the presentation of symptoms can be prevented or delayed.

Optionally, management includes reducing the severity of the disease, reducing the frequency of disease episodes, reducing the duration of such episodes, or reducing the severity of such episodes, or a combination thereof.

Individuals at risk of developing the disease can be identified based on a variety of approaches, either pre-disease or at a fairly early stage in which disease markers can be identified. Identification of at-risk individuals and diagnosis of early-stage disease depend on various approaches, including genomics, proteomics, metabolomics, lipidomics, glycomics, secretomics, serological approaches, and optionally trials involving information processing dysfunction. Obtain (see doi: 10.016 / j. Psychers. 2006.09.014). Family history can also be provided either in combination with one of the approaches described above or as a stand-alone approach. Moreover, in the last decade, microbiome compositions have been recognized as important factors in health and disease. The emergence of new techniques for collating complex microbial communities and in microbiome and metagenomic analysis provides another approach for identifying individuals at risk of developing the disease.

The extracellular lactate levels in astrocytes after treatment with the molecules of the invention from the Prestwick library are shown. The intracellular glycogen levels in astrocytes after treatment with read hits (molecules) from the Prestwick library are shown. The results of the MTT assay in astrocytes after treatment with read hits (molecules) from the Prestwick library are shown. Shows mitochondrial activity in astrocytes after treatment with read hits (molecules) from the Prestwick library. The extracellular lactate levels in astrocytes after treatment with 18 hits (molecules) from the CDC54K library are shown. The intracellular glycogen levels in astrocytes measured 3 hours after stimulation with 18 hits (molecules) from the CDC54K library are shown. The results of body weight monitored for 14 days after acute administration of the drug (100 mg / kg unless otherwise indicated) in C57B 1/6 female mice are shown; n = 6. Body weight of male and female mice during 28 days of chronic treatment with GP-01, GP-02, GP-04, GP-05, GP-06 and GP-07 at 10 mg / kg followed by a 14-day recovery period. Indicates; n> 10. The results of the anxiety test are shown; at the end of chronic treatment, mice were tested for anxiety in an EPM (elevated cross maze). Total distance, open arm approach frequency and dwell time were measured using automatic Ethovation scoring; n> 10. (A) Localization of lactate probe implanted in mouse brain. (B) An example of an intracerebral lactate probe recorded after administration of vehicle and then GP-07 3 hours later is shown. The area under the curve (AUC) was used to calculate the treatment effect (treatment AUC / vehicle AUC). (C to D) Vehicle, then AUC ratio after administration of vehicle or test drug at 10 mg / kg or 100 mg / kg; n = 4-6. Glycogen levels in PFC (prefrontal cortex) 3 hours after oral administration of the drug at 1, 10 or 100 mg / kg; n ≧ 6. GP-04, GP-05, GP-07, GP- in prefrontal cortex microdialysis samples (left panel) and plasma (right panel) before and 30 minutes after administration of the compound (100 mg / kg). The results after measuring the P1 and GP-R1 concentrations are shown; n> 5. GP-04, GP-05, GP-07, GP- in prefrontal cortex microdialysis samples (left panel) and plasma (right panel) before and 30 minutes after administration of the compound (100 mg / kg). The results after measuring the P1 and GP-R1 concentrations are shown; n> 5. Results are shown after treating wild-type or SOD1 female or male mice with vehicle alone or with GP-07 (10 mg / kg) from P30 to sacrifice. Neurological scoring (A), survival (B) and grip strength test (C) are reported group by group (n ≧ 12). The results after administration of GP-07 to male SOD1 mice at 10 mg / kg vs. 100 mg / kg are shown. Shows muscle function (grip strength test) and survival; n ≧ 12. The results of survival, neurological scoring and grip strength tests of male mice treated with 10 mg / kg GP-04 are shown. Similar to the results for the female group; n ≧ 12. Appendix I Appendix I Appendix I Appendix I Appendix I Appendix I Appendix I Appendix I Appendix I Appendix I Appendix I Appendix I Appendix I Appendix I Appendix I Appendix I Appendix I Appendix I Appendix I Appendix I Appendix I Appendix I Appendix I Appendix II Appendix II Appendix II Appendix II Appendix II Appendix II Appendix II

The present invention is, in at least some embodiments, a molecule, a composition comprising the molecule and a method of treatment for the treatment of a neurological disorder, wherein the composition comprises the molecule of the invention described herein. Regarding molecules, compositions and therapeutic methods. Neurological disorders are specifically ALS (Amyotrophic Lateral Sclerosis) and its subtypes. ALS subtypes include medulla oblongata onset ALS and limb onset ALS. In addition to ALS and its subtypes, optionally, the molecules of the invention include, as described herein, primary lateral sclerosis (PLS), progressive medulla oblongata and progressive muscular atrophy. Can be used for the treatment of this type of MND.

（式中、ファミリーＧについて、ＲはＨ、エチルまたはメチルであり、Ｒ１〜Ｒ４は各々独立にＨ、ハロゲン、アルキルまたはアルコキシである）
を含み、
ファミリーＡが、

（式中、Ｒ１はＨまたは非置換もしくは窒素置換のベンジルであり、Ｒ２はＨまたはアルキルであり、但しＲ２がＨである場合、Ｒ１は

ではなく、
さらに但し構造は付録ＩのカタログＩＤ番号Ｆ２２８−０３６５、Ｆ２２８−０３５１、Ｆ２２８−０８５６またはＦ２２８−０５４１のものではない）
を含み、
ファミリーＣが、

（式中、Ｒ１およびＲ２は各々Ｈまたはメトキシであり、Ｒ３、Ｒ４およびＲ５は各々独立にアルキル、好ましくはエチルまたはＨであり、好ましくはＲ３〜Ｒ５の１つのみがアルキル、好ましくはエチルであり、より好ましくはＲ４はアルキル、最も好ましくはエチルであり、
但し構造は付録ＩのカタログＩＤ番号Ｔ５４６４７８２、Ｆ１４６２−０４９１、Ｔ５４６３７０９または４０５２−４２７９のものではない）
を含み、
ファミリーＥが、

（式中、Ｒはペンチル、ベンジル、アルキルベンジルまたはＲ１であり、Ｒ２はアルキル、シクロペンチルまたはシクロブタンであり、Ｒ１は

または

であり、
但し構造は付録ＩのカタログＩＤ番号Ｌ２８７−１５７７またはＬ２８７−１７５８のものではない）
を含み、
ファミリーＦ（７）が、

（式中、Ｒはアルキル、ハロゲンまたはアルコキシであり、
Ｒ１〜Ｒ５は各々独立にＨ、アルキルまたはアルコキシであり、
但し構造は付録ＩのカタログＩＤ番号Ｋ４０４−０６７２、Ｋ４０４−０１８３、Ｋ４０４−０７９６、Ｆ０５２４−０５１１、Ｆ０５２４−０５０７、Ｆ０５２２−０５３３、Ｆ０５２４−０４８８、Ｋ４０４−０４００、Ｔ０５０７−８４４２、Ｋ４０４−０９０６、Ｋ４０４−０８４２、Ｋ４０４−０８５２、Ｋ４０４−０９１４、Ｋ４０４−０９１５、Ｋ４０４−０８２８、Ｋ４０４−０８６３またはＫ４０４−０２７７のものではない）
を含み、
ファミリーＦ（６）が、

（式中、ファミリーＦ（６）について、ＲはＨ、ハロゲン、アルキルまたはアルコキシであり、
Ｒ１、Ｒ２、Ｒ３およびＲ４は各々独立にＨ、アルキルまたはアルコキシであり、但しＲ１がアルコキシである場合、Ｒはアルキルではなく、好ましくはハロゲンまたはアルコキシであり、
但し構造は付録ＩのカタログＩＤ番号Ｋ４０４−０６７２、Ｋ４０４−０１８３、Ｋ４０４−０７９６、Ｆ０５２４−０５１１、Ｆ０５２４−０５０７、Ｆ０５２２−０５３３、Ｆ０５２４−０４８８、Ｋ４０４−０４００、Ｔ０５０７−８４４２、Ｋ４０４−０９０６、Ｋ４０４−０８４２、Ｋ４０４−０８５２、Ｋ４０４−０９１４、Ｋ４０４−０９１５、Ｋ４０４−０８２８、Ｋ４０４−０８６３またはＫ４０４−０２７７のものではない）
を含み、
ファミリーＩが、

（式中、ファミリーＩについて、Ｒは

、または

であり、
ファミリーＩについて、Ｒ１は、非置換またはＳ、ＯもしくはＮ置換のシクロペンタジエンまたはベンゼンであり、Ｒ２はＨまたはカルボニルであり、
ファミリーＩについて、Ｒ１は（各位置での代替原子は角括弧内に示される）

からなる群から選択され、
Ｒ３、Ｒ４およびＲ５は各々独立にＨ、アルキル（好ましくはメチル）および

であり、
但し構造は付録ＩのカタログＩＤ番号Ｔ６３６−２００７、Ｔ６３６−１２５０、Ｔ６３６−２３９１、Ｔ６３６−００５４、Ｔ６３６−００２７、Ｔ６３６−１２４３、Ｔ６３６−２３６０、Ｔ６３６−００８５、Ｔ６３６−０１８１、Ｄ２７８−０５１４、Ｔ６３６−１７１５、Ｔ６３６−２１４４、Ｔ６３６−１６０１またはＴ６３６−０９７３のものではない）
を含み、
ファミリーＭが、

（式中、ＲはＨまたはアルキルであり、アルキルの場合、Ｒは、非置換またはハロゲン（好ましくはＦまたはＣｌ、より好ましくはＦ、好ましくは最大３個のハロゲン）置換のメチルまたはエチル、より好ましくはエチルであり、但し構造は付録ＩのカタログＩＤ番号Ｔ５４３６３７５のものではない）
を含み、
ファミリーＰＱＲＶが（角括弧はその位置での原子がＣまたはＮであってよいことを示す）、

（式中、Ｒ１はベンジル

または

であり、
Ｒ２はアルキルであるか、それが結合する窒素とともに複素環ヘキシル部分を形成するか、または不在であり、
Ｒ３、Ｒ４、Ｒ５およびＲ６は各々ハロゲン、Ｈ、アルキル、（非置換または窒素置換）ベンジルもしくはアルキルベンジル、（ＳもしくはＮ置換または非置換の）シクロペンタジエンもしくはアルキルシクロペンタジエンまたは（任意で、シクロプロパンでアルキル化された）カルバモイルであり、Ｒ４およびＲ５は一緒にＳおよび／もしくはＮ置換または非置換の、かつ任意でアルキル化されたシクロペンタジエンであってよく、
Ｒ７〜Ｒ１１は各々独立にハロゲン、アルキルもしくはメトキシであり、同じであるもしくは異なっていてもよく、またはピロリジン、任意でホルミルピロリジンであり、この場合、好ましくはＲ７はピロリジンであり、
但し構造は付録ＩのカタログＩＤ番号Ｐ０２５−０４６２、Ｐ０２５−００８０、Ｐ０２５−０１６８、Ｔ５５８１４３０、Ｆ０３７６−０２０３またはＴ５２４６４１７のものではなく、
但しＲ１が

である場合、Ｒ２はそれが結合する窒素とともに複素環ヘキシル部分を形成し、
但しＲ１が

である場合、Ｒ７はピロリジンであり、［Ｃ、Ｎ］はＣであり、その場合Ｒ４はＳとＮの両方で置換されたシクロペンタジエンまたはアルキルシクロペンタジエンではなく、
但し、Ｒ１が

である場合、［Ｃ、Ｎ］はＮであり、Ｒ３〜Ｒ６はＨであり、その場合Ｒ７〜Ｒ１１はいずれも、メチル、メトキシまたはハロゲンではなく、
但し、Ｒ１が

である場合、Ｒ７〜Ｒ１１のいずれかは塩素であり、［Ｃ、Ｎ］はＮであり、その場合Ｒ５はカルバモイルではなく、
但し、Ｒ１が

である場合、［Ｃ、Ｎ］はＣであり、Ｒ７〜Ｒ１１のいずれかはハロゲンまたはメトキシであり、Ｒ４およびＲ５は一緒に、Ｓおよび／またはＮ置換シクロペンタジエンを形成し、その場合シクロペンタジエン部分はアルキル化されておらず、またベンジル基を特徴としない）
を含み、
ファミリーＹが、

（式中、Ｒはアルキル、Ｓまたはハロゲン、好ましくはＳまたはハロゲンであり、ハロゲンの場合、好ましくはＦであり、Ｓの場合、好ましくはメチルチオ、またはエチルチオ、最も好ましくはメチルチオであり、
但し構造は付録ＩのカタログＩＤ番号Ｌ９９５−０４０５またはＬ９９５−０３８６のものではない）
を含む、分子が提供される。 According to at least some embodiments, it is a molecule selected from the group consisting of families A, C, E, F (7), F (6), G, I, M, PQRV and Y.
Family G

(In the formula, for family G, R is H, ethyl or methyl, and R1 to R4 are H, halogen, alkyl or alkoxy, respectively).
Including
Family A

(In the formula, if R1 is H or an unsubstituted or nitrogen-substituted benzyl, R2 is H or alkyl, but R2 is H, then R1 is

not,
Further, however, the structure is not that of the catalog ID numbers F228-0365, F228-0351, F228-0856 or F228-0541 of Appendix I).
Including
Family C

(In the formula, R1 and R2 are H or methoxy, respectively, R3, R4 and R5 are each independently alkyl, preferably ethyl or H, preferably only one of R3 to R5 is alkyl, preferably ethyl. Yes, more preferably R4 is alkyl, most preferably ethyl,
However, the structure is not that of the catalog ID numbers T546472, F1462-0491, T5463709 or 4052-4279 of Appendix I).
Including
Family E

(In the formula, R is pentyl, benzyl, alkylbenzyl or R1, R2 is alkyl, cyclopentyl or cyclobutane, and R1 is.

Or

And
However, the structure is not that of the catalog ID number L287-1577 or L287-1758 of Appendix I).
Including
Family F (7)

(In the formula, R is alkyl, halogen or alkoxy,
R1 to R5 are independently H, alkyl or alkoxy, respectively.
However, the structure is the catalog ID numbers K404-0672, K404-0183, K404-0796, F0524-0511, F0524-0507, F0522-0533, F0524-0488, K404-0400, T0507-8442, K404-0906, K404 in Appendix I. Not from -0842, K404-0852, K404-0914, K404-0915, K404-0828, K404-0863 or K404-0277)
Including
Family F (6)

(In the formula, for family F (6), R is H, halogen, alkyl or alkoxy,
R1, R2, R3 and R4 are each independently H, alkyl or alkoxy, where if R1 is alkoxy, then R is not alkyl, preferably halogen or alkoxy.
However, the structure is the catalog ID numbers K404-0672, K404-0183, K404-0796, F0524-0511, F0524-0507, F0522-0533, F0524-0488, K404-0400, T0507-8442, K404-0906, K404 in Appendix I. Not from -0842, K404-0852, K404-0914, K404-0915, K404-0828, K404-0863 or K404-0277)
Including
Family I

(In the ceremony, for Family I, R is

, Or

And
For Family I, R1 is an unsubstituted or S, O or N substituted cyclopentadiene or benzene and R2 is an H or carbonyl.
For Family I, R1 is (alternative atoms at each position are shown in square brackets)

Selected from the group consisting of
R3, R4 and R5 are independently H, alkyl (preferably methyl) and

And
However, the structure is the catalog ID numbers T636-2007, T636-1250, T636-2391, T636-0054, T636-0027, T636-1243, T636-2360, T636-0985, T636-0181, D278-0514, T636 in Appendix I. Not from -1715, T636-2144, T636-1601 or T636-0973)
Including
Family M

(In the formula, R is H or alkyl, where R is unsubstituted or halogen (preferably F or Cl, more preferably F, preferably up to 3 halogens) substituted methyl or ethyl. It is preferably ethyl, but the structure is not that of Appendix I catalog ID number T543365).
Including
The family PQRV (square brackets indicate that the atom at that position may be C or N),

(In the formula, R1 is benzyl

Or

And
R2 is alkyl, forms a heterocyclic hexyl moiety with the nitrogen to which it binds, or is absent.
R3, R4, R5 and R6 are halogen, H, alkyl, (unsubstituted or nitrogen-substituted) benzyl or alkylbenzyl, (S or N-substituted or unsubstituted) cyclopentadiene or alkylcyclopentadiene or (optionally cyclopropane), respectively. (Alkylated with) carbamoyl, where R4 and R5 may be together S and / or N-substituted or unsubstituted, and optionally alkylated cyclopentadiene.
R7 to R11 are each independently halogen, alkyl or methoxy, which may be the same or different, or pyrrolidine, optionally formylpyrrolidine, in which case R7 is preferably pyrrolidine.
However, the structure is not that of the catalog ID numbers P025-0462, P025-0080, P025-0168, T5581430, F0376-0203 or T5246417 of Appendix I.
However, R1

If, R2 forms a heterocyclic hexyl moiety with the nitrogen to which it binds,
However, R1

If R7 is pyrrolidine and [C, N] is C, then R4 is not a cyclopentadiene or alkylcyclopentadiene substituted with both S and N.
However, R1

If, [C, N] is N, R3 to R6 are H, in which case none of R7 to R11 is methyl, methoxy or halogen, and
However, R1

If, any of R7 to R11 is chlorine, [C, N] is N, in which case R5 is not carbamoyl,
However, R1

If, [C, N] is C, any of R7 to R11 is halogen or methoxy, and R4 and R5 together form an S and / or N-substituted cyclopentadiene, in which case cyclopentadiene. The moiety is not alkylated and is not characterized by a benzyl group)
Including
Family Y

(In the formula, R is alkyl, S or halogen, preferably S or halogen, in the case of halogen, preferably F, in the case of S, preferably methylthio or ethylthio, most preferably methylthio.
However, the structure is not that of the catalog ID number L995-0405 or L995-0386 in Appendix I)
Numerator is provided, including.

Optionally, for the above molecules, for family G, R is methyl or ethyl, for R1 to R4, for halogen, one or more of R1 to R4 is F or Cl, and for alkyl, one. Or plural are ethyl or methyl, and in the case of alkoxy, one or more are ethoxy or methoxy,
For family A, R1 is nitrogen-substituted benzyl or H, R2 is H,
For Family C, R1 and R2 are each methoxy, and R3 to R5 are ethyl, respectively, in the case of alkyl.
For family E, if R is pentyl or R1 and R2 is alkyl, then R2 is methyl or ethyl.
For family F (6), if R is halogen, then R is F or Cl, if R is alkyl, then R is methyl or ethyl, and if R is alkoxy, then R is methoxy or ethoxy. Yes,
If any of R1 to R5 is alkyl, it is methyl, if any of R1 to R5 is alkoxy, it is methoxy or ethoxy, but if R1 is alkoxy, then R is not alkyl and It is preferably halogen or alkoxy,
For family F (7), if R is alkyl, then R is ethyl or methyl, if R is halogen, then R is Cl or F, and if R is alkoxy, then R is methoxy or ethoxy. If any of R1 to R5 is alkyl, it is methyl, and if any of R1 to R5 is alkoxy, it is methoxy or ethoxy.
For family M, where R is alkyl, then R is an unsubstituted or halogen-substituted methyl or ethyl.
For family Y, if R is alkyl, then R is ethyl or methyl, if R is S, then R is methylthio or ethylthio, and if R is halogen, then R is F.

Optionally, for the above molecules, for family G, R1 to R4 are methyl for alkyl and methoxy for alkoxy, respectively.
For Family C, only one of R3 to R5 is ethyl and the rest is H.
For family M, if R is alkyl, then R is ethyl and
For family Y, R is S or halogen.

Optionally, for the above molecules, for family G, at least two of R1 to R4 are halogens, at least two are alkyls, one is alkoxy, and one is alkyl, one is alkyl. And one is H and one is halogen and one is H, or one is alkoxy and one is H.
For family C, R4 is ethyl, R3 and R5 are H,
For family M, where R is ethyl, R is substituted with F or Cl, more preferably F, preferably up to 3 halogens.
For family Y, if R is S, then R is methylthio.

Optionally, for the above molecules, for Family G, the molecule is selected from the group consisting of G1 to G6 in Appendix I (Cat. No. L924-1031; L924-1088; L924-0830; L924-0760; L924-0884; Or a molecule having L924-0988),
For Family A, the molecule is selected from the group consisting of A1 to A3 in Appendix I (molecules with catalog numbers F228-0422, F228-0350 or F228-0534).
For Family C, molecules are selected from the group consisting of C1 to C3 in Appendix I (molecules with catalog numbers T5463586, 4052-4304 or T546658).
For Family E, molecules are selected from the group consisting of E1 to E4 in Appendix I (molecules with catalog numbers L287-0468, L287-1641, L287-1221 and L287-0220).
For family F (6), the molecule is selected from the group consisting of F4 to F6, F8, F9, F13 of Appendix I (catalog numbers K404-0800, K404-0673, F0524-0338, K404-0685, K404-0697). And molecules with K404-0394),
For family F (7), the molecule is selected from the group consisting of F1-F3, F7, F10-F12 in Appendix I (catalog numbers K404-0834, K404-0838, K404-0885, K404-0910, K404-0855). , K404-0860 and F0524-0611),
For Family I, the molecule is selected from the group consisting of I1-I5 and I7 of Appendix I (Molecules having Catalog Nos. T636-1937, T636-1114, T636-2387, T636-0134, T636-1210 and T636-2425. ),
For Family M, molecules are selected from the group consisting of M1 and M2 in Appendix I (molecules with catalog numbers T5599014 and T5653029).
For family PQRV, the molecule is selected from the group consisting of P1, Q1-Q3, R1, V1 and V2 of Appendix I (molecules with catalog numbers P025-0159, T564489, T5599698, T5618591, T5580243, T6937001 and T5511047).
For family Y, the molecule is selected from the group consisting of Y1 and Y2 in Appendix I (molecules with catalog numbers L995-0125 and L995-0058).

According to at least some embodiments, pharmaceutical compositions comprising the above molecules are provided.

The molecule or pharmaceutical composition is optionally used as a drug.

The molecule or pharmaceutical composition can be used for the treatment of neurological disorders, which include ALS (Amyotrophic Lateral Sclerosis), a subtype thereof or related disorders. ALS subtypes include medulla oblongata onset ALS and limb onset ALS. In addition to ALS and its subtypes, optionally, the molecules of the invention are used for the treatment of other types of MND, including primary lateral sclerosis (PLS), progressive medulla oblongata and progressive muscular atrophy. Can be. Optionally, subtypes include medulla oblongata onset ALS and limb onset ALS. Optionally, related disorders include primary lateral sclerosis (PLS), progressive medulla oblongata and progressive muscular atrophy.

Optionally, a method for treating a mammal in need thereof, comprising administering to the mammal the above-mentioned molecule or pharmaceutical composition of the invention for the treatment of a neurological disorder. Methods are provided in which the disease comprises ALS (Amyotrophic Lateral Sclerosis) and its subtypes. ALS subtypes include medulla oblongata onset ALS and limb onset ALS. In addition to ALS and its subtypes, optionally, the molecules of the invention are used for the treatment of other types of MND, including primary lateral sclerosis (PLS), progressive medulla oblongata and progressive muscular atrophy. Can be.

（式中、Ｒ１はＨまたは非置換もしくは窒素置換のベンジルであり、Ｒ２はＨまたはアルキル、好ましくはＨであり、但しＲ２がＨである場合、Ｒ１は

ではなく、
さらに但し構造は付録ＩのカタログＩＤ番号Ｆ２２８−０３６５、Ｆ２２８−０３５１、Ｆ２２８−０８５６またはＦ２２８−０５４１のものではない）
を有し、
ファミリーＣの分子が構造、

（式中、Ｒ１およびＲ２は各々Ｈまたはメトキシ、好ましくはメトキシであり、Ｒ３、Ｒ４およびＲ５は各々独立にアルキル、好ましくはエチルまたはＨであり、好ましくはＲ３〜Ｒ５の１つのみがアルキル、好ましくはエチルであり、残りはＨであり、より好ましくはＲ４はアルキル、最も好ましくはエチルであり、Ｒ３およびＲ５はＨであり、
但し構造は、付録ＩのカタログＩＤ番号Ｔ５４６４７８２、Ｆ１４６２−０４９１、Ｔ５４６３７０９または４０５２−４２７９のものではない）
を有し、
ファミリーＥの分子が構造、

（式中、Ｒはペンチル、ベンジル、アルキルベンジルまたはＲ１、好ましくはペンチルまたはＲ１であり、Ｒ２はアルキル、シクロペンチルまたはシクロブタンであり、Ｒ２がアルキルである場合、好ましくはメチルまたはエチルであり、
Ｒ１は

または

であり、但し構造は付録ＩのカタログＩＤ番号Ｌ２８７−１５７７またはＬ２８７−１７５８のものではない）
を有し、
ファミリーＩが構造、

（式中、ファミリーＩについて、Ｒは

または

であり、
ファミリーＩについて、Ｒ１は非置換またはＳ、ＯもしくはＮ置換のシクロペンタジエンまたはベンゼンであり、Ｒ２はＨまたはカルボニルであり、
ファミリーＩについてＲ１は（各位置での代替原子は角括弧内に示されている）

からなる群から選択され、
Ｒ３、Ｒ４およびＲ５は各々独立にＨ、アルキル（好ましくはメチル）および

であり、
但し構造は付録ＩのカタログＩＤ番号Ｔ６３６−２００７、Ｔ６３６−１２５０、Ｔ６３６−２３９１、Ｔ６３６−００５４、Ｔ６３６−００２７、Ｔ６３６−１２４３、Ｔ６３６−２３６０、Ｔ６３６−００８５、Ｔ６３６−０１８１、Ｄ２７８−０５１４、Ｔ６３６−１７１５、Ｔ６３６−２１４４、Ｔ６３６−１６０１またはＴ６３６−０９７３のものではない）
を有し、
ファミリーＦ（６）の分子が構造、

（式中、ファミリーＦ（６）について、ＲはＨ、ハロゲン、好ましくはＦまたはＣｌ；アルキル、好ましくはメチルまたはエチル；アルコキシ、好ましくはメトキシまたはエトキシであり、
Ｒ１、Ｒ２、Ｒ３およびＲ４は各々独立にＨ、アルキル、好ましくはメチルまたはエチル；アルコキシ、好ましくはメトキシまたはエトキシであり、但しＲ１がアルコキシである場合、Ｒはアルキルではなく、好ましくはハロゲンまたはアルコキシであり、
但し構造は、付録ＩのカタログＩＤ番号Ｋ４０４−０６７２、Ｋ４０４−０１８３、Ｋ４０４−０７９６、Ｆ０５２４−０５１１、Ｆ０５２４−０５０７、Ｆ０５２２−０５３３、Ｆ０５２４−０４８８、Ｋ４０４−０４００、Ｔ０５０７−８４４２、Ｋ４０４−０９０６、Ｋ４０４−０８４２、Ｋ４０４−０８５２、Ｋ４０４−０９１４、Ｋ４０４−０９１５、Ｋ４０４−０８２８、Ｋ４０４−０８６３またはＫ４０４−０２７７のものではない）
を有し、
ファミリーＦ（７）の分子が構造、

（式中、Ｒはアルキル、好ましくはエチルまたはメチル；ハロゲン、好ましくはＣｌまたはＦ；Ｈ；アルコキシ、好ましくはメトキシまたはエトキシであり、
Ｒ１〜Ｒ５は各々独立にＨ、アルキル、好ましくはメチル；アルコキシ、好ましくはメトキシまたはエトキシであり、
但し構造は、付録ＩのカタログＩＤ番号Ｋ４０４−０６７２、Ｋ４０４−０１８３、Ｋ４０４−０７９６、Ｆ０５２４−０５１１、Ｆ０５２４−０５０７、Ｆ０５２２−０５３３、Ｆ０５２４−０４８８、Ｋ４０４−０４００、Ｔ０５０７−８４４２、Ｋ４０４−０９０６、Ｋ４０４−０８４２、Ｋ４０４−０８５２、Ｋ４０４−０９１４、Ｋ４０４−０９１５、Ｋ４０４−０８２８、Ｋ４０４−０８６３またはＫ４０４−０２７７のものではない）
を有し、
ファミリーＭの分子が構造、

（式中、ＲはＨまたはアルキルであり、アルキルの場合、Ｒは非置換またはハロゲン（好ましくはＦまたはＣｌ、より好ましくはＦ、好ましくは最大３個のハロゲン）置換のメチルまたはエチル、より好ましくはエチルであり、
但し構造は付録ＩのカタログＩＤ番号Ｔ５４３６３７５のものではない）
を有し、
ファミリーＰＱＲＶが（角括弧はその位置での原子がＣまたはＮであってよいことを示す）構造、

（式中、Ｒ１はベンジル

または

であり、
Ｒ２はアルキルであるか、それが結合する窒素とともに複素環ヘキシル部分を形成するか、または不在であり、
Ｒ３、Ｒ４、Ｒ５およびＲ６は各々ハロゲン、Ｈ、アルキル、（非置換または窒素置換の）ベンジルもしくはアルキルベンジル、（ＳもしくはＮ置換または非置換の）シクロペンタジエンもしくはアルキルシクロペンタジエンまたは（任意で、シクロプロパンでアルキル化された）カルバモイルであり、Ｒ４およびＲ５は一緒に、Ｓおよび／もしくはＮ置換または非置換の、かつ任意でアルキル化されたシクロペンタジエンであってもよく、
Ｒ７〜Ｒ１１は各々独立にハロゲン、アルキルもしくはメトキシであり、同一もしくは異なっていてもよく、またはピロリジン、任意でホルミルピロリジンであり、この場合、好ましくはＲ７はピロリジンであり、
但し構造は付録ＩのカタログＩＤ番号Ｐ０２５−０４６２、Ｐ０２５−００８０、Ｐ０２５−０１６８、Ｔ５５８１４３０、Ｆ０３７６−０２０３またはＴ５２４６４１７のものではない）
を有し、
ファミリーＹの分子が構造、

（式中、Ｒはアルキル、Ｓまたはハロゲン、好ましくはＳまたはハロゲンであり、ハロゲンの場合、好ましくはＦであり、Ｓの場合、好ましくはメチルチオまたはエチルチオ、最も好ましくはメチルチオであり、
但し構造は付録ＩのカタログＩＤ番号Ｌ９９５−０４０５またはＬ９９５−０３８６のものではない）上記分子と、
付録Ｉに記載の分子からなる群から選択される本発明の分子であって、上記分子が、カタログＩＤ番号Ｔ０５０２−５５６０；Ｔ０５０８−５１９０、Ｔ２０２−１４５５、Ｔ２０２−０９７３、Ｋ８５１−０１１３、Ｔ５６３０３０９、Ｔ５６７２３８０、Ｔ５９６７３８９、Ｔ５８８４０３８、Ｔ５２３１４２４、Ｔ０５１７−８２５０、Ｔ０５１１−９２００およびＴ５６２７７２１からなる群から選択される、上記分子と、
本明細書の表１に示す分子と、
付録ＩＩに記載の分子であって、上記分子がカタログＩＤ番号Ｔ６０１０７８９、Ｔ５９９３７９９、Ｔ５８１３０８５、Ｔ６９４７８４８、Ｔ０５１７−４１１７、Ｔ５７２９５５７、Ｔ５７０５５２２、Ｚ６０６−８３５２、ＬＩ１５−０４０３、Ｔ５７１２０７１、Ｔ５７９０４７６、Ｔ５７８８３３９、Ｇ４３３−０２９３、Ｔ５７１９２５７、Ｔ５７９８７６１、Ｔ５８２１７２３、Ｔ５７８７５２６、Ｔ５８２７５９４、Ｋ４０５−２５９５、Ｔ５２７４９５９、Ｍ９５０−１５１５、Ｔ５４５０２３９、Ｇ５０８−００１５、Ｔ５７０７２３０、Ｔ５７１０３４３、８８７−０１８３、Ｔ５４５３９２３、Ｔ０５０５−４０８７、Ｔ５６７３３２２、Ｔ５８００６０７、Ｇ８６９−００７１、Ｆ２７９４−０１２８、Ｔ０５００−６６２９、Ｔ５８３２７６４、Ｍ５０８−０３７０、Ｔ０５１５−１７８３、Ｔ５３９３５００、Ｔ５６７２３８０、Ｍ３８１−０７３０、Ｚ６０６−８２８７、Ｇ８５５−０１４３、Ｚ０７６−００２８、Ｔ５３１１２００、Ｅ９４４−０１８２、Ｌ３０２−００６９、Ｔ５７７０６４０、Ｇ８６９−００６４、Ｔ５７５３１６５、Ｇ８５５−０１８３、Ｔ５３２９７２３、Ｔ５３３２６０、Ｌ９３２−０２６７、Ｌ３０２−０１８１、Ｔ５４４４０８３、Ｔ６１２５２５１、Ｔ５６９４３２９、Ｔ０５１７−２７８３、Ｔ５７８８５４５、Ｔ５５８６０９１、Ｔ５９６７３８９、Ｔ５７８３７９４、Ｔ５４９４３５２、Ｔ５４７７６９６、Ｐ６２１−１３６４、Ｙ０３１−０３６１、Ｔ５３１８８３３、Ｚ６０６−８３５１、Ｔ５６０６３８７、Ｔ０５１６−６８９４、Ｔ５６９１８９６、Ｚ６０６−８２９８、Ｆ５２８５−００６９、Ｔ９９３−１７８７、Ｚ６０６−５３４１、Ｆ３３９４−１３６４、Ｙ０３０−２８３２、Ｔ５４００２３４、Ｔ５３８９５１７、Ｚ６０３−８０３７、Ｔ０５１３−０２１３、およびＴ６３６−２３８７からなる群から選択される、上記分子と、
または、付録ＩもしくはＩＩの分子構造に関連し、本明細書に記載の少なくとも１つのアッセイにおいて好適な代謝活性を有する分子
からなる群から選択される、上記分子または医薬組成物が提供される。 According to at least some embodiments, the molecule of the invention or a pharmaceutical composition comprising it for the treatment of a neurological disorder, wherein the neurological disorder is ALS (Amyotrophic Lateral Sclerosis), a sub. The above molecules include types or related diseases:
A molecule of the invention selected from the group consisting of families A, C, E, F (7), F (6), G, I, M, PQRV and Y.
Family A molecule is the structure,

(In the formula, R1 is H or an unsubstituted or nitrogen-substituted benzyl, R2 is H or alkyl, preferably H, where R2 is H, then R1 is

not,
Further, however, the structure is not that of the catalog ID numbers F228-0365, F228-0351, F228-0856 or F228-0541 of Appendix I).
Have,
Family C molecule is the structure,

(In the formula, R1 and R2 are H or methoxy, preferably methoxy, respectively, R3, R4 and R5 are each independently alkyl, preferably ethyl or H, preferably only one of R3 to R5 is alkyl, Preferably ethyl, the rest is H, more preferably R4 is alkyl, most preferably ethyl, and R3 and R5 are H.
However, the structure is not that of the catalog ID numbers T5464782, F1462-0491, T5463709 or 4052-4279 of Appendix I).
Have,
Family E molecule is the structure,

(In the formula, R is pentyl, benzyl, alkylbenzyl or R1, preferably pentyl or R1, R2 is alkyl, cyclopentyl or cyclobutane, and when R2 is alkyl, it is preferably methyl or ethyl.
R1 is

Or

However, the structure is not that of the catalog ID number L287-1577 or L287-1758 of Appendix I).
Have,
Family I is the structure,

(In the ceremony, for Family I, R is

Or

And
For Family I, R1 is an unsubstituted or S, O or N substituted cyclopentadiene or benzene and R2 is an H or carbonyl.
For Family I R1 (alternative atoms at each position are shown in square brackets)

Selected from the group consisting of
R3, R4 and R5 are independently H, alkyl (preferably methyl) and

And
However, the structure is the catalog ID numbers T636-2007, T636-1250, T636-2391, T636-0054, T636-0027, T636-1243, T636-2360, T636-0985, T636-0181, D278-0514, T636 in Appendix I. Not from -1715, T636-2144, T636-1601 or T636-0973)
Have,
The structure of the family F (6) molecule,

(In the formula, for family F (6), R is H, halogen, preferably F or Cl; alkyl, preferably methyl or ethyl; alkoxy, preferably methoxy or ethoxy.
R1, R2, R3 and R4 are independently H, alkyl, preferably methyl or ethyl; alkoxy, preferably methoxy or ethoxy, where if R1 is alkoxy, then R is not alkyl, preferably halogen or alkoxy. And
However, the structure is as follows: Catalog ID numbers K404-0672, K404-0183, K404-0796, F0524-0511, F0524-0507, F0522-0533, F0524-0488, K404-0400, T0507-8442, K404-0906, in Appendix I. Not from K404-0842, K404-0852, K404-0914, K404-0915, K404-0828, K404-0863 or K404-0277)
Have,
The structure of the family F (7) molecule,

(In the formula, R is alkyl, preferably ethyl or methyl; halogen, preferably Cl or F; H; alkoxy, preferably methoxy or ethoxy.
R1 to R5 are independently H, alkyl, preferably methyl; alkoxy, preferably methoxy or ethoxy, respectively.
However, the structure is as follows: Catalog ID numbers K404-0672, K404-0183, K404-0796, F0524-0511, F0524-0507, F0522-0533, F0524-0488, K404-0400, T0507-8442, K404-0906, in Appendix I. Not from K404-0842, K404-0852, K404-0914, K404-0915, K404-0828, K404-0863 or K404-0277)
Have,
Family M molecule is the structure,

(In the formula, R is H or alkyl, where R is unsubstituted or halogen (preferably F or Cl, more preferably F, preferably up to 3 halogens) substituted methyl or ethyl, more preferably. Is ethyl
However, the structure is not that of the catalog ID number T543365 of Appendix I)
Have,
The structure of the family PQRV (square brackets indicate that the atom at that position may be C or N),

(In the formula, R1 is benzyl

Or

And
R2 is alkyl, forms a heterocyclic hexyl moiety with the nitrogen to which it binds, or is absent.
R3, R4, R5 and R6 are halogen, H, alkyl, benzyl or alkylbenzyl (unsubstituted or nitrogen-substituted), cyclopentadiene (S or N-substituted or unsubstituted) or cyclopentadiene or (optionally cyclo) It is a carbamoyl (alkylated with propane), and R4 and R5 may be together S and / or N-substituted or unsubstituted, and optionally alkylated cyclopentadiene.
R7 to R11 are each independently halogen, alkyl or methoxy and may be the same or different, or pyrrolidine, optionally formylpyrrolidine, in which case R7 is preferably pyrrolidine.
However, the structure is not that of the catalog ID numbers P025-0462, P025-0080, P025-0168, T5581430, F0376-0203 or T5246417 of Appendix I).
Have,
Family Y molecule is the structure,

(In the formula, R is alkyl, S or halogen, preferably S or halogen, in the case of halogen, preferably F, in the case of S, preferably methylthio or ethylthio, most preferably methylthio.
However, the structure is not that of the catalog ID number L995-0405 or L995-0386 in Appendix I.)
A molecule of the invention selected from the group consisting of the molecules described in Appendix I, wherein the molecule is Catalog ID No. T0502-5560; T0508-5190, T202-1455, T202-0973, K851-0113, T563309, With the above molecule selected from the group consisting of T5672380, T5967389, T588038, T5231424, T0517-8250, T0511-9200 and T5627721.
The molecules shown in Table 1 of the present specification and
The molecules described in Appendix II, the molecules of which are Catalog ID Nos. T601079, T5993799, T5813085, T6947848, T0517-4117, T5729557, T570552, Z606-8352, LI15-0403, T5712071, T5790476, T5788339, G433-0293, T5719257, T5798761, T5821723, T5787526, T58275994, K405-2595, T5274959, M950-1515, T545302, G508-0015, T5707230, T5710343, 887-0183, T5453923, T0505-4087, T567573232, T0505-4087, T567 0128, T0500-6629, T5832764, M508-0370, T0515-1783, T5393500, T5672380, M381-0730, Z606-8287, G855-0143, Z076-0028, T5311200, E944-0182, L302-0069, T5770640, G869- 0064, T5753165, G855-0183, T53529723, T533260, L932-0267, L302-0181, T5444083, T6125251, T5694329, T0517-2783, T5788545, T5586091, T5967389, T5783794, T54943552, 037467 T5318833, Z606-8351, T5606387, T0516-6894, T5691896, Z606-8298, F5285-0069, T993-1787, Z606-5341, F3394-1364, Y030-2832, T540234, T5389517, Z603-8037, T0513-0213 And the molecule selected from the group consisting of T636-2387, and
Alternatively, said molecule or pharmaceutical composition is provided that is selected from the group consisting of molecules that are related to the molecular structure of Appendix I or II and that have suitable metabolic activity in at least one of the assays described herein.

である場合、Ｒ２が、それが結合する窒素とともに複素環ヘキシル部分を形成し、
但し、Ｒ１が

である場合、Ｒ７がピロリジンであり、［Ｃ、Ｎ］がＣであり、その場合Ｒ４がＳとＮの両方で置換されたシクロペンタジエンまたはアルキルシクロペンタジエンではなく、
但し、Ｒ１が

である場合、［Ｃ、Ｎ］がＮであり、Ｒ３〜Ｒ６がＨであり、その場合Ｒ７〜Ｒ１１がいずれも、メチル、メトキシまたはハロゲンではなく、
但し、Ｒ１が

である場合、Ｒ７〜Ｒ１１のいずれかが塩素であり、［Ｃ、Ｎ］がＮであり、その場合Ｒ５がカルバモイルではなく、
但し、Ｒ１が

である場合、［Ｃ、Ｎ］がＣであり、Ｒ７〜Ｒ１１のいずれかがハロゲンまたはメトキシであり、Ｒ４およびＲ５が一緒にＳおよび／またはＮ置換シクロペンタジエンを形成し、その場合シクロペンタジエン部分がアルキル化されておらず、またベンジル基を特徴とせず、
ファミリーＩについて、Ｒ６が不在である、
上記の分子またはそれを含む医薬組成物。 Optionally, for family PQRV, R2 is alkyl, forms a heterocyclic hexyl moiety with the nitrogen to which it binds, or is absent.
R3, R4, R5 and R6 are halogen, H, alkyl, benzyl or alkylbenzyl (unsubstituted or nitrogen-substituted), cyclopentadiene (S or N-substituted or unsubstituted) or alkylcyclopentadiene (optionally cyclo), respectively. It is a carbamoyl (alkylated with propane), and R4 and R5 may be together S and / or N-substituted or unsubstituted, and optionally alkylated cyclopentadiene.
R7 to R11 are each independently halogen, alkyl or methoxy and may be the same or different, or pyrrolidine, optionally formylpyrrolidine, in which case R7 is preferably pyrrolidine.
However, the structure is not that of the catalog ID numbers P025-0462, P025-0080, P025-0168, T5581430, F0376-0203 or T5246417 of Appendix I.
However, R1

If, R2 forms a heterocyclic hexyl moiety with the nitrogen to which it binds,
However, R1

If R7 is pyrrolidine and [C, N] is C, then R4 is not a cyclopentadiene or alkylcyclopentadiene substituted with both S and N.
However, R1

If [C, N] is N and R3 to R6 are H, then none of R7 to R11 is methyl, methoxy or halogen,
However, R1

If, one of R7 to R11 is chlorine, [C, N] is N, in which case R5 is not carbamoyl,
However, R1

If [C, N] is C, any of R7 to R11 is halogen or methoxy, and R4 and R5 together form an S and / or N-substituted cyclopentadiene, in which case the cyclopentadiene moiety. Is not alkylated and is not characterized by a benzyl group,
For Family I, R6 is absent,
The above molecule or a pharmaceutical composition containing the above molecule.

Optionally, for family G, R is methyl or ethyl, for R1 to R4, for halogen, one or more of R1 to R4 is F or Cl, and for alkyl, one or more is ethyl or Methyl, in the case of alkoxy, one or more are ethoxy or methoxy,
For family A, R1 is nitrogen-substituted benzyl or H, R2 is H,
For Family C, R1 and R2 are methoxy, respectively, and R3 to R5 are ethyl if each is alkyl.
For family E, if R is pentyl or R1 and R2 is alkyl, then R2 is methyl or ethyl and
For family F (6), if R is halogen, R is F or Cl, R is alkyl, R is methyl or ethyl, R is alkoxy, then R is methoxy or ethoxy. Yes,
When any of R1 to R5 is alkyl, it is methyl, and when any of R1 to R5 is alkoxy, it is methoxy or ethoxy, except that when R1 is alkoxy, R is not alkyl and is preferable. Is halogen or alkoxy,
For family F (7), if R is alkyl, R is ethyl or methyl, R is halogen, R is Cl or F, and R is alkoxy, then R is methoxy or ethoxy. Yes, if any of R1 to R5 is alkyl, it is methyl, and if any of R1 to R5 is alkoxy, it is methoxy or ethoxy.
For family M, where R is alkyl, then R is unsubstituted or halogen-substituted methyl or ethyl.
For family Y, if R is alkyl, then R is ethyl or methyl, if R is S, then R is methylthio or ethylthio, and if R is halogen, then R is F.
The above molecule or a pharmaceutical composition containing the above molecule.

Optionally, for Family G, R1 to R4 are each methyl if alkyl and methoxy if alkoxy.
For Family C, one of R3 to R5 is ethyl and the rest is H.
For family M, if R is alkyl, then R is ethyl and
For family Y, R is S or halogen,
The above molecule or a pharmaceutical composition containing the above molecule.

Optionally, for Family G, at least two of R1 to R4 are halogens, at least two are alkyls, one is alkoxy and one is alkyl, one is alkyl and one is H, 1 One is halogen and one is H, or one is alkoxy and one is H.
For family C, R4 is ethyl, R3 and R5 are H,
For family M, where R is ethyl, R is substituted with F or Cl, more preferably F, preferably up to 3 halogens.
For family Y, if R is S, then R is methylthio,
The above molecule or a pharmaceutical composition containing the above molecule.

Optionally, for Family G, the numerator is selected from the group consisting of G1 to G6 in Appendix I (Cat. No. L924-1031; L924-1088; L924-0830; L924-0760; L924-0884; or L924-0888. Molecules),
For Family A, molecules are selected from the group consisting of A1 to A3 in Appendix I (molecules with catalog numbers F228-0422, F228-0350 or F228-0534).
For Family C, molecules are selected from the group consisting of C1 to C3 in Appendix I (molecules with catalog numbers T5463586, 4052-4304 or T546658).
For Family E, molecules are selected from the group consisting of E1 to E4 in Appendix I (molecules with catalog numbers L287-0468, L287-1641, L287-1221 and L287-0220).
For family F (6), the numerator is selected from the group consisting of F4 to F6, F8, F9, F13 of Appendix I (catalog numbers K404-0800, K404-0673, F0524-0338, K404-0685, K404-0697). And molecules with K404-0394),
For family F (7), the numerator is selected from the group consisting of F1-F3, F7, F10-F12 in Appendix I (catalog numbers K404-0834, K404-0838, K404-0885, K404-0910, K404-0855). , K404-0860 and F0524-0611),
For Family I, the molecule is selected from the group consisting of I1-I5 and I7 of Appendix I (Molecules with Catalog Numbers T636-1937, T636-1114, T636-2387, T636-0134, T636-1210 and T636-2425. ),
For Family M, molecules are selected from the group consisting of M1 and M2 in Appendix I (molecules with catalog numbers T5599014 and T5653029).
For family PQRV, molecules are selected from the group consisting of P1, Q1-Q3, R1, V1 and V2 in Appendix I (molecules with catalog numbers P025-0159, T564489, T5599698, T5618591, T5580243, T69337001 and T5511047).
For family Y, the numerator is selected from the group consisting of Y1 and Y2 in Appendix I (molecules with catalog numbers L995-0125 and L995-0058).
The above molecule or a pharmaceutical composition containing the above molecule.

According to at least some embodiments, a method of treating a mammal in need of that treatment, wherein the molecule or pharmaceutical composition of the invention described above for the treatment of a neurological disorder is administered to the mammal. The above methods are provided, wherein the neurological disorder comprises ALS (Amyotrophic Lateral Sclerosis), its subtypes and related disorders. Optionally, the subtypes include medulla oblongata-onset ALS and limb-onset ALS. Optionally, related disorders include one of primary lateral sclerosis (PLS), progressive medulla oblongata or progressive muscular atrophy.

The molecule, pharmaceutical composition or method described above that can be used or can be used to delay the onset of a disease in an individual at risk of developing the disease according to one or more predictive markers.

The molecule is in the family PQRV, except that the molecule is thieno [3,2-c] pyridine-2-sulfonamide, 5-acetyl-4,5,6,7-tetrahydro-N- (phenylmethyl)-; thieno. [3,2-c] pyridine-2-sulfonamide, 5-acetyl-4,5,6,7-tetrahydro-N-[(3-methoxyphenyl) methyl]-; thieno [3,2-c] pyridine- 2-sulfonamide, 5- (cyclopropylcarbonyl) -4,5,6,7-tetrahydro-N- [3- (methylthio) phenyl]-; thieno [3,2-c] pyridine-2-sulfonamide, 5-acetyl-N- (2,5-dimethylphenyl) -4,5,6,7-tetrahydro-; thieno [3,2-c] pyridine-2-sulfonamide, 5-acetyl-N- (2, 5-Dimethylphenyl) -4,5,6,7-tetrahydro-; thieno [3,2-c] pyridine-2-sulfonamide, 5- (cyclopropylcarbonyl) -N- (3-fluoro-4-methyl) Phenyl) -4,5,6,7-tetrahydro-; thieno [3,2-c] pyridine-2-sulfonamide, 5-acetyl-N- (2,5-dimethylphenyl) -4,5,6 7-Tetrahydro; thieno [3,2-c] pyridine-2-sulfonamide, 5-acetyl-N- (2,5-dimethylphenyl) -4,5,6,7-tetrahydro; thieno [3,2 -C] Pyridin-2-sulfonamide, 5-acetyl-N- (2,5-dimethylphenyl) -4,5,6,7-tetrahydro-; thieno [3,2-c] pyridine-2-sulfonamide , 5- (Cyclopropylcarbonyl) -4,5,6,7-tetrahydro-N- [3- (methylthio) phenyl]-; thieno [3,2-c] pyridine-2-sulfonamide, 5-acetyl -N- (2,5-dimethylphenyl) -4,5,6,7-tetrahydro-; thieno [3,2-c] pyridine-2-sulfonamide, 5- (cyclopropylcarbonyl) -N- (3) -Fluoro-4-methylphenyl) -4,5,6,7-The above-mentioned molecule, pharmaceutical composition or method containing no tetrahydro.

Optionally, the molecule, pharmaceutical composition or method provides treatment, including increased energy metabolism in the nervous system.

For example, it is understood that the molecules shown in Appendix I that are toxic or inactive in one or more assays are not the molecules of the invention described herein, as shown by the test results shown herein. To. However, even such molecules are active when given in small amounts (for toxic molecules) or in large amounts or in different forms (for molecules that are inactive in one or more assays). It may be possible.

The invention also includes variants and derivatives of the above compounds, including tautomers, degradative enantiomers, diastereomers, solvates, biotransformers, salts and pharmaceutically acceptable prodrugs. Offer different forms.

Specific terms are defined first so that the present invention can be more easily understood. Further definitions are given throughout the detailed description.

In the present specification, when a plurality of consecutive integer values are described, it is assumed that the sequence includes all integer values between each integer value.

The terms "individual", "host", "subject" and "patient" are used interchangeably herein to refer to any human or non-human animal. The term "non-human animal" includes all vertebrates such as mammals and non-mammals such as non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, insects and the like.

The various aspects of the invention are described in more detail in the following subsections.

Therapeutic Methods As mentioned above, the molecules of the invention described herein can be used to treat the neurological disorders described herein.

Therefore, according to a further aspect of the invention, a method of treating a neurological disorder is provided. Specifically, neurological disorders include ALS (Amyotrophic Lateral Sclerosis) and its subtypes. ALS subtypes include medulla oblongata onset ALS and limb onset ALS. In addition to ALS and its subtypes, optionally, the molecules of the invention can be used for the treatment of primary lateral sclerosis (PLS), progressive medulla oblongata and progressive muscular atrophy.

As used herein, the term "treatment" refers to the prevention, delay, cure, amelioration, attenuation, alleviation, minimization, suppression or arrest of adverse effects of any of the above diseases, disorders or conditions. This also includes the management of the above diseases. "Management" means reducing the severity of the disease, reducing the frequency of disease episodes, shortening the duration of such episodes, reducing the severity of such episodes, and the like.

The treatment according to the invention can be achieved by specifically administering to the subject at least one of the molecules of the invention of the invention.

The molecules of the invention can optionally be administered as part of a pharmaceutical composition described in more detail below.

Therapeutic Uses According to at least some embodiments, new uses and treatments for neurological disorders are provided by administering the molecules of the invention in therapeutically effective amounts to subjects in need of their treatment. ..

The amount to be administered depends on the therapeutic need and can be readily determined by one of ordinary skill in the art according to the efficacy of the molecules described herein.

Neurological Disorders and Disorders Treated The neurological disorders and disorders that can be treated using the molecules of the invention are described herein. These diseases include ALS (Amyotrophic Lateral Sclerosis) and its subtypes. ALS subtypes include medulla oblongata onset ALS and limb onset ALS. In addition to ALS and its subtypes, optionally, the molecules of the invention can be used for the treatment of primary lateral sclerosis (PLS), progressive medulla oblongata and progressive muscular atrophy.

Amyotrophic Lateral Sclerosis-ALS
ALS is a lethal motor neuron disease characterized by progressive loss of upper and lower motor neurons at the spinal and medulla oblongata levels. ALS is classified into two forms. The most common form is sporadic (90-95%), which has no apparent genetically inherited components. The remaining 5-10% of cases are familial ALS (FALS) due to the dominant genetic factors of their associated genes. Disease incidence of about 1 / 100,000. The first onset of symptoms is usually 50-65 years. The most common symptoms that appear in both types of ALS are weakness, spasms and muscle spasms, which can ultimately lead to muscle dysfunction, progressive muscle atrophy and paralysis, and there is no effective treatment. Therefore, patients typically die within 3-5 years of diagnosis (Haverkamp, Appel, & Appel, 1995).

Symptoms and Prognosis of ALS Amyotrophic Lateral Sclerosis (ALS) is a heterogeneous group of neurodegenerative diseases characterized by progressive loss of motor nerves, resulting in weakness, paralysis and ultimately death. .. Both upper motor neurons (brain) and lower motor neurons (spinal cord) are typically involved.

Patients typically present with limb onset (80% of cases) or medulla oblongata onset (20% of cases). In limb-onset cases, symptoms appear distal or proximal to either the upper or lower limbs. Medulla oblongata usually manifests with dysarthria and dysphagia, and limb symptoms can occur with medulla oblongata or at the appropriate time of the disease within a year. The typical age of onset is about 55 years. It progresses at a fast pace, with many patients dying within 3-5 years of onset. However, there are also a few ALS cases with a relatively gradual course of disease. The incidence of the disease is similar worldwide, ranging from 1-2 new cases per 100,000 people each year, with a prevalence of about 4-6 cases per 100,000 people.

Diagnosis of ALS There is no single definitive diagnostic test for ALS. Certain diagnostic tests may be directed to rule out the possibility of ALS, but generally only muscle activity and nerve conduction tests provide evidence of ALS in patients. Electromyography (EMG) is used to determine the electrical activity of muscle fibers. Nerve conduction studies (NCS) measure the electrical activity of nerves and muscles by assessing the ability of nerves to signal along or to muscles.

There are several specific criteria for the diagnosis of ALS known as L-Escorial criteria. According to the L Escorial criteria, the diagnosis of ALS requires:
Signs of lower motor neuron degeneration in the spinal cord and brainstem by laboratory or special studies;
Laboratory-examined signs of upper motor neuron degeneration in the brain;
• Progressive spread of signs within one area to another;
• Absence of evidence of other disease processes that can explain the observed clinical and electrophysiological signs.

ALS Biomarkers There are currently no ALS biomarkers, but certain genetic abnormalities are found in some patient groups. As described in Chen et al. ("Genetics of amyotrophic lateral sclerosis: an update", Mol Neurodigener. 2013; 8:28), there are multiple mutations found in different ALS cases. 90% of ALS cases are sporadic familial cases with different genotypes. The editorials are related to superoxide dismutase 1 (SOD1), TAR DNA-binding protein (TARDBP), fusion sarcoma (FUS), ubiquilin 2 (UBQLN2), C9ORF72, arsin, senataxin (SETX), spataxin, vesicle-related membrane protein It is noted that mutations in protein B (VABP), angiogenin (ANG), factor-inducing gene 4 (FIG4) and optineurin (OPTN) were all found in ALS patients with familial disease. Other gene mutations may be involved.

Mechanism of action of ALS The mechanism of action of ALS is unknown, and in fact, various etiologies may be involved due to various disease-related genetic mutations and environmental factors. However, researchers have found that dysfunction of oligodendrocytes and astrocytes can at least contribute to the pathology of ALS.

Oligodendrocytes support axonal survival and function through mechanisms unrelated to myelination, and their dysfunction results in axonal degeneration. Lee et al. ("Oligodendroglia metabolically support axes and control to neurodegeneration", Nature. July 26, 2012; 487 (7408): 443-448) are expressed in oligodendrocytes, oligodendrocytes, and oligodendrocytes. Destruction of monocarboxylic acid transporter 1 (MCT1) has been demonstrated to cause axonal damage and neuronal loss in animal and cell culture models. In addition, this transporter is reduced in patients with amyotrophic lateral sclerosis (ALS) and their mouse models, suggesting a role for oligodendrocyte MCT1 in pathogenesis. Therefore, disruption of lactate metabolism can at least contribute to the pathology of ALS. Treating such destruction can potentially treat ALS, at least resulting in reduced symptoms or delayed onset of such symptoms.

Astrocytes have been suggested to be potential drug targets for motor neuron diseases and generally neurodegenerative diseases (Finsterwald et al., "Astr Neurogenerative Diseases", Currant Pharmaceutical Design, 2015, 21, 3570-3581). Astrocytes are especially important for maintaining normal neuronal metabolism. These cells are involved in the removal of glutamate in the synaptic cleft and the initiation of the astrocyte neuron lactate shuttle (ANLS), among other things. Without ANLS, the transfer of lactate from astrocytes to neurons is not maintained, resulting in impaired energy metabolism in the nervous system. Again, as mentioned above, disruption of lactate metabolism can at least contribute to the pathology of ALS. Treating such destruction can potentially treat ALS, resulting in at least a reduction in symptoms or a delay in the onset of such symptoms.

Compounds of the Invention The compounds of the invention may have one or more asymmetric centers. Thus, such compounds can be produced as individual (R) or (S) stereoisomers, or as mixtures thereof. Unless otherwise stated, the description or naming of a particular compound in the specification and claims is intended to include both the individual enantiomers and diastereomers and their racemic or other mixtures thereof. Will be done. Thus, the invention also includes all such isomers, including diastereomeric mixtures of the compounds of the invention, pure diastereomers and pure enantiomers. The term "enantiomer" refers to two stereoisomers of a compound that are mirror images of each other. The term "diastereomer" refers to a pair of optical isomers that are not mirror images of each other. Diastereomers have various physical properties such as melting point, boiling point, spectral properties and reactivity.

The compounds of the invention may also exist in various tautomeric forms, all of which are within the scope of the invention. The term "tautomer" or "tautomer" refers to structural isomers of various energies that can be interconverted through a low energy barrier. For example, proton tautomers (also known as prototropy tautomers) include interconversion through proton transfer, such as keto-enol and imine-enamine isomerization. Valence tautomers include interconversion by rearrangement of some bound electrons.

Unless the stereochemistry of any particular chiral atom is specified in the structures shown herein, all stereoisomers are contemplated and included as compounds of the invention. If the stereochemistry is specified by a solid wedge or dashed line representing a particular arrangement, then this stereoisomer is specified and defined as such.

The compounds of the present invention include solvates of such compounds, pharmaceutically acceptable prodrugs and salts (including pharmaceutically acceptable salts).

The phrase "pharmaceutically acceptable" means that the substance or composition is chemically and / or toxicologically compatible with the other components that make up the formulation and / or the mammal being treated with it. Shown.

"Solvate" refers to an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine. The term "hydrate" can also be used to refer to a complex in which the solvent molecule is water.

A "prodrug" is a compound that can be converted to a specified compound or to a salt of such a compound under physiological conditions or by solvolysis. A prodrug is an amino acid residue, or a polypeptide chain of two or more (eg, 2, 3 or 4) amino acid residues, via an amide or ester bond, the free amino, hydroxy or of the compounds of the invention. Contains compounds covalently attached to carboxylic acid groups. Amino acid residues include, but are not limited to, 20 naturally occurring amino acids commonly designated by three letter symbols, and amino acid residues are also phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxy. Lysine, Demosin, Isodemocin, γ-carboxyglutamate, Horseuric acid, Octahydroindole-2-carboxylic acid, Stat, 1,2,3,4-Tetrahydroisoquinolin-3-carboxylic acid, Penicillamine, Ornitine, 3-Methylhistidine , Norvarin, β-alanine, γ-aminobutyric acid, silturin, homocysteine, homoserine, methylalanine, para-benzoylphenylalanine, phenylglycin, propargylglycine, sarcosin, methionine sulfone and tert-butylglycine.

Further types of prodrugs are also included. For example, the free carboxyl groups of the compounds of the invention can be derivatized as amides or alkyl esters. As another example, the compounds of the present invention containing free hydroxyl groups are described in D.I. A group such as, but not limited to, a hydroxyl group, such as, but not limited to, a phosphate ester, a hemicouccinic acid, a dimethylaminoacetate or a phosphoryloxymethyloxycarbonyl group, as outlined in Freesher, Advanced Prodrug Delivery Reviews, 1996, 19, 115. By converting to, it can be derivatized as a prodrug. Hydroxy and amino group carbamate prodrugs are also included, as are hydroxy group carbonate prodrugs, sulfonic acid esters and sulfate esters. The acyl group can be an alkyl ester optionally substituted with a group comprising, but not limited to, ether, amine and carboxylic acid functional groups, or the acyl group is the amino acid ester described above, (acyloxy) methyl and (acyloxy) methyl and (. Derivatization of hydroxy groups as acyloxy) ethyl ethers is also included. This type of prodrug is J. Med. Chem. , 1996, 39, 10. More specific examples include (C1-C6) alkanoyloxymethyl, 1-((C1-C6)) alkanoyloxy) ethyl, 1-methyl-1-((C1-C6) alkanoyloxy) ethyl, (C1). ~ C6) alkoxycarbonyloxymethyl, N- (C1-C6) alkoxycarbonylaminomethyl, succinoyl, (C1-C6) alkanoyl, α-amino ((C1-C4) alkanoyl, arylacyl and α-aminoacyl, or α- It involves the replacement of the hydrogen atom of the alcohol group with a radical such as aminoacyl-α-aminoacyl, where each α-aminoacyl group is a naturally occurring L-amino acid, P (O) (OH) 2, -P (O). ) (C1-C6) alkyl) 2 or glycosyl (radicals resulting from the removal of the hydroxyl group in the hemiacetal form of the amino acid).

Free amines of such compounds can also be derivatized as amides, sulfonamides or phosphonamides. All of these moieties may incorporate groups including, but not limited to, ether, amine and carboxylic acid functional groups. For example, prodrugs are groups such as R-carbonyl, RO-carbonyl, NRR'-carbonyl (in the formula, R and R'are independently (C1-C10) alkyl, (C3-C7) cycloalkyl or benzyl, respectively. There, or R-carbonyl is a natural α-aminoacyl or a natural α-aminoacyl-a natural α-aminoacyl), -C (OH) C (O) OY (in the formula, Y is H, (C1). ~ C6) alkyl or benzyl), -C (OY0) Y1 (in the formula, Y0 is (C1-C4) alkyl, Y1 is (C1-C6) alkyl, carboxy (C1-C6) alkyl, amino ( C1-C4) alkyl or mono-N or di-N, N- (C1-C6) alkylaminoalkyl), or -C (Y2) Y3 (in the formula, Y2 is H or methyl and Y3 is mono. It can be formed by the replacement of hydrogen atoms in the amine group with −N or di-N, N- (C1-C6) alkylamino, morpholino, piperidine-1-yl or pyrrolidine-1-yl).

Further examples of prodrug derivatives are specifically incorporated herein by reference, respectively, eg, a) Design of Prodrugs, H. et al. Edited by Bundgaad, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, pp. 309-396, K. et al. Edited by Wider et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, Krogsgard-Larsen and H. et al. Edited by Bundgard, H.M. Chapter 5, "Design and Application of Prodrugs," by Bundgaard, pp. 113-191 (1991); c) H. et al. Bundgaard, Advanced Drug Delivery Reviews, 8: 1-38 (1992); d) H. et al. Bundgaard et al., Journal of Pharmaceutical Sciences, 77: 285 (1988); and e) N. et al. Kakeya et al., Chem. Pharm. Bull. , 32: 692 (1984).

Alternatively or additionally, the compounds of the invention may have a fully acidic group, a fully basic group or both functional groups and thus react with any number of inorganic or organic bases or acids. Can form salts. Examples of salts include salts prepared by the reaction of the compounds of the present invention with mineral or organic acids, such as sulfates, pyrosulfates, hydrogen sulfates, sulfites, hydrogen sulfites, phosphates, phosphorus. Monohydrogen Acid, Dihydrogen Phosphate, Metaphosphate, Pyrophosphate, Chloride, Bromide, Iodine, Acetate, Propionate, Decanoate, Caprilate, Acrylate, Gate, Isobutyrate , Capronate, heptaneate, propiolate, oxalate, malonate, succinate, subephosphate, sebacate, fumarate, maleate, butin-1,4-diate , Hexin-1,6-diate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfone Acids, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1- Examples include salts including, but not limited to, sulfonates, naphthalene-2-sulfonates and mandelates. Since a single compound of the invention may contain more than one acidic or basic moiety, the compounds of the invention may contain mono, di or tri-salts in a single compound.

When the compound of the invention is a base, the desired salt can be any suitable method available in the art, eg, a free base, an acidic compound, eg, an inorganic acid, eg, hydrochloric acid, an odor. Hydrogenated acid, sulfuric acid, nitrate, phosphoric acid, etc., or organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvate, oxalic acid, glycolic acid, salicylic acid, pyranosidilic acid, for example , Glucroic acid or galacturonic acid, α-hydroxy acid, eg citric acid or tartaric acid, amino acids, eg aspartic acid or glutamate, aromatic acids, eg benzoic acid or cinnamic acid, sulfonic acid, eg p-toluenesulfonic acid Alternatively, it can be prepared by treating with ethanesulfonic acid or the like.

When the compound of the invention is an acid, the desired salt can be prepared by any suitable method, for example by treating the free acid with an inorganic or organic base. Examples of suitable inorganic salts include salts formed of alkaline and alkaline earth metals such as lithium, sodium, potassium, barium and calcium. Examples of suitable organic base salts include salts such as ammonium, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, bis (2-hydroxyethyl) ammonium, phenylethylbenzylamine, dibenzylethylenediamine and the like. .. Other salts of the acidic moiety include, for example, these salts formed of procaine, quinine and N-methylglucosamine, as well as basic amino acids such as glycine, ornithine, histidine, phenylglycine, lysine and arginine. You can mention salt.

In certain embodiments, the salt is a "pharmaceutically acceptable salt", which retains the biological effectiveness of the corresponding free acid or base of the specified compound, unless otherwise indicated. Contains salts that are biologically or otherwise undesired.

As described herein, the compounds of the invention are also not necessarily pharmaceutically acceptable salts, and for the preparation and / or purification of such compounds, and / or of such compounds. Includes other salts of such compounds that may be useful as intermediates for separating enantiomers.

Pharmaceutical Compositions The present invention, in some embodiments, comprises a pharmaceutical composition comprising a therapeutically effective amount of a therapeutic agent according to the invention. According to the present invention, the therapeutic agent is the molecule of the present invention described herein. The therapeutic agents of the present invention may be provided to a subject alone or as part of a pharmaceutical composition in which they are mixed with a pharmaceutically acceptable carrier.

As used herein, "pharmaceutically acceptable carrier" includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption retarders, and the like. Including. Preferably, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal cord, mucosal (including nasal) or epidermal administration (eg, by injection or infusion). Depending on the route of administration, the active compound may include one or more pharmaceutically acceptable salts. "Pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the parent compound and does not exert any undesired toxic effects (eg, Berge, SM et al. (1977) J. Pharm. Sci). See .66: 1-19). Examples of such salts include acid addition salts and base addition salts. Acid addition salts include those derived from non-toxic inorganic acids such as hydrochloric acid, nitrate, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phobic acid and the like, as well as non-toxic organic acids such as Examples include those derived from aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like. Base addition salts include those derived from alkaline earth metals such as sodium, potassium, magnesium, calcium and the like, and non-toxic organic amines such as N, N'-dibenzylethylenediamine, N-methylglucamine. Examples thereof include those derived from chloroprocine, choline, diethanolamine, ethylenediamine, prokine and the like.

Pharmaceutical compositions according to at least some embodiments of the invention may also contain pharmaceutically acceptable antioxidants. Examples of pharmaceutically acceptable antioxidants are: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium hydrogensulfate, sodium metahydrosulfate, sodium sulfite, etc .; (2) oil-soluble. Antioxidants such as ascorbic palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol and the like; and (3) metal chelating agents such as citrate, Examples thereof include ethylenediaminetetraacetic acid (EDTA), sorbitol, tartrate acid, and phosphoric acid. Pharmaceutical compositions according to at least some embodiments of the invention are also additives such as detergents and solubilizers (eg TWEEN20 (polysorbate 20), TWEEN80 (polysorbate 80)), preservatives (eg thimerosal, benzyl). Alcohol) as well as excipients (eg, lactose, mannitol) may be included.

Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions according to at least some embodiments of the invention are water, various buffer components (eg, tris-HCl, acetates, phosphates). , PH and ionic strength buffered saline, ethanol, polyols (eg, glycerol, propylene glycol, polyethylene glycol, etc.), suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Can be mentioned.

Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, in the case of dispersion by the maintenance of the required particle size, and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersants. Prevention of the presence of microorganisms can be ensured by both the sterilization procedure described above and the inclusion of various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include isotonic agents, such as sugar, sodium chloride, etc. in the composition. In addition, long-term absorption of injectable pharmaceutical forms can be provided by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersants and sterile powders for the immediate preparation of sterile injectable solutions or dispersants. The use of such media and agents for pharmaceutically active substances is known in the art. Its use in pharmaceutical compositions according to at least some embodiments of the invention is contemplated, except where any conventional medium or agent is incompatible with the active compound. Auxiliary active compounds can also be incorporated into the composition.

The therapeutic composition typically must be sterile and stable under manufacturing and storage conditions. The composition can be formulated as a solution, microemulsion, liposome or other ordered structure suitable for high drug concentrations. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyols (eg, glycerol, propylene glycol, liquid polyethylene glycol, etc.), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required grain shape in the case of dispersion, and by the use of surfactants. In many cases, it is preferred that the composition comprises an isotonic agent, such as sugar, polyalcohol, such as mannitol, sorbitol or sodium chloride. Long-term absorption of the injectable composition can be achieved by including agents that delay absorption, such as monostearate and gelatin, in the composition. Sterile injectable solutions can be prepared by incorporating the active compound in the required amount into a suitable solvent having one or a combination of the components listed above and, if necessary, performing sterile microfiltration. Dispersants are generally prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and other necessary components from those listed above. For sterile powders for the preparation of sterile injectable solutions, the preferred method of preparation is vacuum drying and freeze-drying, resulting in a powder of the active ingredient, plus any additional desired ingredient powder from a pre-sterile filtered solution. It is dry (freeze-dried).

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount into a suitable solvent having one or a combination of the components listed above and, if necessary, performing sterile microfiltration. Dispersants are generally prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and other necessary components from those listed above. For sterile powders for the preparation of sterile injectable solutions, the preferred method of preparation is vacuum drying and freeze-drying, resulting in a powder of the active ingredient, plus any additional desired ingredient powder from a pre-sterile filtered solution. It is dry (freeze-dried).

The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending on the subject being treated and the particular mode of administration. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form is generally the amount of composition that provides a therapeutic effect. Optionally, of 100%, this amount in combination with a pharmaceutically acceptable carrier is about 0.01% to about 99%, preferably about 0.1% to about 70%, most preferably about 1% to. It is in the range of about 30% active ingredient.

The dosage regimen is adjusted to provide the optimal desired response (eg, therapeutic response). For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the emergency of the treatment situation. It is particularly advantageous to formulate parenteral compositions into unit dosage forms for ease of administration and uniformity of dosage. Unit dosage forms as used herein refer to physically separate units suitable as unit dosages for the subject being treated, each unit in collaboration with the required pharmaceutical carrier to achieve the desired therapeutic effect. Contains a predetermined amount of active compound calculated in. The specification of unit dosage forms according to at least some embodiments of the present invention is such that (a) the unique properties of the active compound and the particular therapeutic effect to be achieved, and (b) the treatment of individual susceptibility. Directly dependent on, and directly dependent on, the technical field-specific constraints of formulating active compounds.

The compositions of the present invention can be administered via one or more routes of administration using one or more of the various methods known in the art. As will be appreciated by those skilled in the art, routes of administration and / or modes of administration will vary depending on the desired outcome. Preferred routes of administration for therapeutic agents according to at least some embodiments of the invention are intravascular delivery (eg, injection or infusion), intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal cord, oral, intestinal. , Rectal, lung (eg, inhalation), nasal, topical (including transdermal, buccal and sublingual), intravesical, vitreous, intraperitoneal, vaginal, intracerebral delivery (eg, intraventricular, intracerebral and Convection enhanced diffusion), CNS delivery (eg, sublingual, peri-spinal and intra-spinal), or parenteral (including subcutaneous, intramuscular, intraperitoneal, intravenous (IV) and intradermal), transdermal (passive) Target or either by injection or use of electroporation), transmucosal (eg, sublingual, nasal, vaginal, rectal or sublingual) administration or via implant, or other parenteral administration Routes include, for example, injection or infusion, or other routes of delivery and / or modes of administration known in the art.

As used herein, the term "parenteral administration" refers to a mode of administration by conventional injection other than intestinal and topical administration, including intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraocular, and cardiac. These include intradermal, intradermal, intraperitoneal, transtracheal, subcutaneous, subepithelial, intra-articular, subcapsular, submucosal, intraspinal, epidural and intrathoracic injections and injections, or the use of biodegradable inserts. It can be formulated in a dosage form suitable for each administration route. In certain embodiments, the molecules of the invention or pharmaceutical compositions comprising them according to at least some embodiments of the invention can be administered intraperitoneally or intravenously.

The compositions of the invention, when delivered as either aerosols or spray-dried particles with an aerodynamic diameter of less than about 5 microns, are delivered to the lungs with inhalation and reach the bloodstream across the lining of the lung epithelium. Can be. A wide range of mechanical devices designed for pulmonary delivery of therapeutic products can be used, including, but not limited to, nebulizers, metered dose inhalers and powder inhalers, all of which are familiar to those skilled in the art. Some specific examples of commercially available devices include Ultravent nebulizers (Mallinckrod, Inc., St. Louis, Mo.); Acorn II nebulizers (Marquest Medical Products, Englewood, Color.); Ventrin quantitative inhalers (Glaxo Inc.). , Research Triangle Park, NC); and Spinhaler powder inhalers (Fisons Corp., Bedford, Mass.). Nektar, Alkermes and Mankind all have inhalable insulin powder preparations that have been approved or are in clinical trials, and the technique can be applied to the formulations described herein.

In some in vivo approaches, the compositions disclosed herein are administered to a subject in therapeutically effective amounts. As used herein, the term "effective amount" or "therapeutically effective amount" is the pharmacologically desired to treat, inhibit or alleviate one or more symptoms of the disorder being treated, or otherwise desired. And / or means a dosage sufficient to produce a physiological effect. The exact dosage depends on various factors, such as subject-dependent variables (eg, age, immune system health, etc.), disease, and treatment given. As further research is conducted on the molecules of the invention described herein and compositions containing them, information on dosage levels suitable for the treatment of different conditions in different patients will be revealed to those skilled in the art. Appropriate dosing will be confirmed, taking into account the recipient's therapeutic background, age and general health.

The dosage selected will depend on the desired therapeutic effect, route of administration and desired duration of treatment. For example, a daily dosage level of 0.0001-100 mg / kg body weight, more specifically 0.001-20 mg / kg, can be administered to the mammal. For example, the dosage can be 0.3 mg / kg body weight, 1 mg / kg body weight, 3 mg / kg body weight, 5 mg / kg body weight or 10 mg / kg body weight, or can be in the range of 1-10 mg / kg. An exemplary treatment plan is once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every three months, or three to six. Accompanied by administration once a month. In general, the dosage for intravenous injection or infusion may be small. The dosage regimen is adjusted to provide the optimal desired response (eg, therapeutic response). For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by an emergency in the treatment situation. It is particularly advantageous to formulate parenteral compositions into unit dosage forms for ease of administration and uniformity of dosage. Unit dosage forms as used herein refer to physically separate units suitable as unit dosages for the subject being treated, where each unit achieves the desired therapeutic effect in collaboration with the required pharmaceutical carrier. Contains a predetermined amount of active compound calculated to be. The specification of unit dosage forms according to at least some embodiments of the present invention is such that (a) the unique properties of the active compound and the particular therapeutic effect to be achieved, and (b) the treatment of individual susceptibility. Directly dependent on, and directly dependent on, the technical field-specific constraints of formulating active compounds.

Optionally, the pharmaceutical formulation may be administered in an amount of 0.0001-100 mg / kg patient body weight / day, preferably 0.001-20.0 mg / kg / day, depending on any suitable timing regimen. Therapeutic compositions according to at least some embodiments of the invention are described, for example, three times a day, twice a day, once a day, three times a week, twice a week or once a week. It can be administered once every 2 weeks or every 3, 4, 5, 6, 7 or 8 weeks. In addition, the composition can be administered for short or long periods of time (eg, 1 week, 1 month, 1 year, 5 years).

Alternatively, the therapeutic agent can be administered as a sustained release formulation, in which case less frequent administration is required. Dosage and frequency will vary depending on the half-life of the therapeutic agent in the patient. The half-lives of molecules can vary widely. Dosage and frequency can vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, relatively low dosages are administered at relatively infrequent intervals over a long period of time. Some patients continue to receive treatment for the rest of their lives. In therapeutic applications, relatively high dosages at relatively short intervals until the progression of the disease is reduced or terminated, preferably until the patient exhibits partial or complete remission of the symptoms of the disease. Often needed. The patient can then be given a prophylactic plan.

The actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention is an active ingredient effective in achieving the desired therapeutic response to a particular patient, composition and mode of administration without being toxic to the patient. Can vary as the amount of is obtained. The dosage level selected is used in combination with the activity of the particular composition of the invention used, the route of administration, the duration of administration, the rate of excretion of the particular compound used, the duration of treatment, the particular composition used. Depends on various pharmacokinetic factors including other drugs, compounds and / or materials, age, gender, weight, condition of the patient being treated, general health and medical history, and similar factors well known in the medical field. To do.

The "therapeutically effective dosages" of the molecules of the invention are preferably reduced in severity of disease symptoms, increased frequency and duration of asymptomatic disease periods, extended lifespan, remission of disease, or disability due to distress of disease. Or it brings about prevention or reduction of physical disability.

One of ordinary skill in the art will be able to determine a therapeutically effective amount based on factors such as the size of the subject, the severity of the subject's symptoms, and the particular composition or route of administration selected.

In certain embodiments, the pharmaceutical composition is administered topically, for example, by direct injection into the site to be treated. Typically, injection increases the local concentration of the pharmaceutical composition, which is higher than the concentration achievable by systemic administration. For example, in the case of neurological disorders, the molecules of the invention can be locally administered to a site near the CNS.

The pharmaceutical composition of the present invention can be administered by a medical device known in the art. For example, in an optional embodiment, the pharmaceutical composition according to at least some embodiments of the invention is a needle or other subcutaneous injection device, such as US Pat. No. 5,399,163, US Pat. No. 5,383. , 851, US Pat. No. 5,312,335, US Pat. No. 5,064,413, US Pat. No. 4,941,880, US Pat. No. 4,790,824, or US Pat. No. 4, It can be administered by the device disclosed in 596,556. Examples of well-known implants and modules useful in the present invention are: US Pat. No. 4,487,603, which discloses an implantable microinjection pump for delivering a drug at a controlled rate; US Pat. No. 4,486,194, which discloses a therapeutic device for delivering a drug; US Pat. No. 4,447,233, which discloses a drug infusion pump for delivering a drug at an accurate infusion rate; for continuous drug delivery. US Pat. No. 4,447,224 disclosing variable flow implantable infusion devices for; US Pat. No. 4,439,196 disclosing osmotic drug delivery systems with multichamber compartments; and osmotic drug delivery. US Pat. No. 4,475,196, which discloses the system. These patent documents are incorporated herein by reference. Many other such implants, delivery systems and modules are known in the art.

The active compound can be prepared with a carrier that protects the compound from rapid release, such as controlled release formulations, including implants, transdermal patches and microencapsulated delivery systems. Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polyacetic acid can be used. Many methods of preparing such formulations have been patented or are generally known to those of skill in the art. For example, Sustained and Controlled Release Drug Delivery Systems, J. Mol. R. Robinson ed., Marcel Dekker, Inc. , New York, 1978.

The therapeutic composition can be administered by a medical device known in the art. For example, in an optional embodiment, the therapeutic composition according to at least some embodiments of the invention is a needle or subcutaneous injection device, such as US Pat. No. 5,399,163, US Pat. No. 5,383,851. No., US Pat. No. 5,312,335, US Pat. No. 5,064,413, US Pat. No. 4,941,880, US Pat. No. 4,790,824, or US Pat. No. 4,596. It can be administered by the device disclosed in No. 556. Examples of well-known implants and modules useful in the present invention are: US Pat. No. 4,487,603, which discloses an implantable microinjection pump for delivering a drug at a controlled rate, administering the drug through the skin. US Pat. No. 4,486,194, which discloses a therapeutic device for delivering a drug; US Pat. No. 4,447,233, which discloses a drug infusion pump for delivering a drug at an accurate infusion rate; for continuous drug delivery. US Pat. No. 4,447,224 disclosing variable flow implantable infusion devices for; US Pat. No. 4,439,196 disclosing osmotic drug delivery systems with multichamber compartments; and osmotic drug delivery. US Pat. No. 4,475,196, which discloses the system. These patent documents are incorporated herein by reference. Many other such implants, delivery systems and modules are known to those of skill in the art.

In certain embodiments, therapeutic agents according to at least some embodiments of the invention can be formulated to ensure proper distribution in vivo. For example, the blood-brain barrier (BBB) eliminates many highly hydrophilic compounds. To ensure that therapeutic compounds according to at least some embodiments of the invention cross the BBB (if desired), they can be formulated, for example, in liposomes. See, for example, US Pat. No. 4,522,811, US Pat. No. 5,374,548, and US Pat. No. 5,399,331 for methods of producing liposomes. Liposomes may contain one or more moieties that are selectively transported to a particular cell or organ and thus may enhance targeted drug delivery (eg, VV Rande (1989) J. Mol. See Clin. Pharmacol. 29: 685). Illustrative target moieties include folic acid or biotin (see, eg, US Pat. No. 5,416,016 to Low et al.); Mannoside (Umezawa et al., (1988) Biochem. Biophyss. Res. Commun. 153: 1038); Antibodies (PG Bloeman et al. (1995) FEBS Lett. 357: 140; M. Owais et al. (1995) Antimiclob. Agents Chemother. 39: 180); Surfactant protein A receptor (Briscoe et al. (1995) Am. J. Physiol. 1233: 134), pl20 (Schreier et al. (1994) J. Biol. Chem. 269: 9090). Keinanen; L. Laukkanen (1994) FEBS Lett. 346: 123, J. Mol. J. Killion; I. J. See also Fiddler (1994) Immunohomes 4: 273.

Formulations for Parenteral Administration In a further embodiment, the pharmaceutical compositions disclosed herein are administered in aqueous solution by parenteral injection. The formulation can also be in the form of suspensions or emulsions. Generally, pharmaceutical compositions are provided comprising an effective amount of the molecule of the invention as described herein and are optionally pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants. And / or includes carriers. Such compositions optionally include one or more of the following: diluents, sterile water, various buffer components (eg, tris-HCl, acetate, phosphate), pH and ionic strength buffers. Hydrochloride, and additives such as detergents and solubilizers (eg, TWEEN20 (polysolvate-20), TWEEN80 (polysolvate-80)), antioxidants (eg, water-soluble antioxidants, such as ascorbic acid, hydrochloride). Sodium hydrogen sulfite, cysteine hydrochloride, sodium hydrogen sulfate, sodium metahydrosulfate, sodium sulfite, etc .; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxytoluene (BHA), butylated hydroxytoluene (BHT), lecithin , Chrysanthemate propyl acid, α-tocopherol; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid), and preservatives (eg timerosar, benzyl alcohol) and bulking substances (eg, timerosar, benzyl alcohol). For example, lactose, mannitol). Examples of non-aqueous solvents or vehicles are ethanol, propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. The formulation can be freeze-dried or vacuum dried and redissolved / resuspended immediately prior to use. The formulation can be sterilized, for example, by filtering through a bacterial retention filter, incorporating a sterilizing agent into the composition, irradiating the composition, or heating the composition.

Formulations for Topical Administration The molecules of the invention disclosed herein are preferably applied topically to one or more of the lungs, nose, mouth (sublingual, buccal), vaginal or rectal mucosa. obtain.

When delivered as either an aerosol or spray-dried particles having an aerodynamic diameter of less than about 5 microns, the composition can be delivered to the lungs with inhalation and reach the bloodstream across the lining of the lung epithelium.

A wide range of mechanical devices designed for pulmonary delivery of therapeutic products can be used, including, but not limited to, nebulizers, metered dose inhalers and powder inhalers, all of which are familiar to those skilled in the art. Some specific examples of commercially available devices include Ultravent nebulizers (Mallinckrod, Inc., St. Louis, Mo.); Acorn II nebulizers (Marquest Medical Products, Englewood, Color.); Ventrin quantitative inhalers (Glaxo Inc.). , Research Triangle Park, NC); and Spinhaler powder inhalers (Fisons Corp., Bedford, Mass.). Nektar, Alkermes and Mankind all have approved or inhalable insulin powder preparations in clinical trials, all have inhalable insulin powder preparations in approved or clinical trials, the techniques are described herein. Can be applied to the described formulations.

Formulations for mucosal administration are typically spray-dried drug particles, which can be incorporated into tablets, gels, capsules, suspensions or emulsions. Standard pharmaceutical excipients are available from any formulation technician. Oral formulations can be in the form of chewing gum, gel strips, tablets or lozenges.

Transdermal formulations can also be prepared. These are typically ointments, lotions, sprays or patches, all of which can be prepared using standard techniques. Transdermal preparations should include a penetration enhancer.

Controlled Delivery Polymer Matrix The molecules of the invention disclosed herein can also be administered in controlled release formulations. Controlled release polymer devices can be manufactured for long-term systemic release after implantation of polymer devices (rods, cylinders, films, discs) or after injection (microparticles). The matrix can be in the form of microparticles such as microspheres, where the molecules of the invention are dispersed within a solid polymer matrix or microcapsules, and the core is of a different material than the polymer shell, according to the invention. The molecule is dispersed or suspended in the core, which can be liquid or solid in nature. Unless specifically defined herein, microparticles, microspheres and microcapsules are used interchangeably. Alternatively, the polymer can be cast as a thin slab or film in the range of nanometers to 4 centimeters, as a powder produced by grinding or other standard techniques, or even as a gel such as hydrogel.

Both non-biodegradable or biodegradable matrices can be used for delivery of the molecules of the invention, but biodegradable matrices are preferred. These can be natural or synthetic polymers, but synthetic polymers are preferred due to their good characterization of degradation and release profiles. The polymer is selected based on the desired duration of release. In some cases linear emission may be most useful, but in other cases pulse emission or "bulk emission" may give more effective results. The polymer can be in the form of a hydrogel (typically absorbing up to about 90% by weight of water) and can optionally be crosslinked with polyvalent ions or polymers.

The matrix can be formed by solvent evaporation, spray drying, solvent extraction and other methods known to those of skill in the art. Bioerosive microspheres are described, for example, by Mathiowitz and Langer, J. Mol. Controlled Release, 5: 13-22 (1987); Mathiowitz et al., Reactive Polymers, 6: 275-283 (1987); and Mathiowitz et al., J. Mol. Apple. Polymer Sci. It can be prepared using any of the methods developed for producing microspheres for drug delivery, described in 35: 755-774 (1988).

The device can be formulated for topical release to treat the area of implantation or injection, which typically delivers a dosage well below the dosage for systemic treatment or systemic delivery. These can be implanted in muscle, fat, injected subcutaneously, or swallowed.

Combination Therapy It will be recognized that the treatment of the above diseases according to the present invention can be combined with other treatment methods known in the art (ie, combination therapy). Thus, therapeutic agents and / or pharmaceutical compositions containing them according to at least some embodiments of the invention listed herein can also be used in combination with one or more of the following agents: Riluzole and edaravone can be used in combination with any of the molecules of the invention described herein.

Other combinations will be readily recognized and understood by those skilled in the art. In some embodiments, therapeutic agents are used to attenuate or ameliorate the activity of drugs suitable for the treatment of the neurological disorders described herein and / or limit the adverse effects of such drugs. obtain.

As will be readily appreciated by those skilled in the art, the combination is a therapeutic agent according to at least some embodiments of the invention and / or a pharmaceutical composition comprising it and one other drug; listed herein. Therapeutic agents and / or pharmaceutical compositions containing them and two other drugs; the therapeutic agents and / or pharmaceutical compositions containing them listed herein, and three other drugs and the like. it can. The determination of the optimal combination and dosage can be determined and optimized using methods well known in the art.

The therapeutic agent according to the invention and one or more other therapeutic agents can be administered either sequentially or simultaneously.

The therapeutic agents listed herein and / or pharmaceutical compositions comprising them according to at least some embodiments of the invention are combined with another therapy, eg, as described above herein. Of course, the dosage of the co-administered drug will vary depending on the type of codrug used, the particular drug used, the condition being treated, and the like.

The treatment of neurological disorders using the agents of the present invention can be combined with other therapeutic methods known in the art that are non-pharmacological treatments. Examples of such non-drug therapies include non-drug therapies, including mechanical ventilation, whether invasive or non-invasive.

Example 1-Testing Materials and Methods for Molecules of the Invention on ALS 1. All mouse animal experiments were performed according to the Swiss Federal Guideline for Animal Experimentation and were approved by the Swiss Clinical Veterinary Office for Animal Experimentation.

2. 2. Cell Culture Primary cultures of cerebral cortical astrocytes were obtained from 1-2 year old OF1 pups (Charles River Laboratories). Simply put, the cortex was isolated and chopped into small pieces under an anatomical microscope. Cells were incubated at 37 ° C. for 30 minutes in a solution containing 20 U / ml papain enzyme (Worthington Biochemical), 1 mM L-cysteine (Sigma) and 10 kU / ml DNase I (Worthington Biochemical) for enzyme dissociation. Papine activity was stopped by adding fetal bovine serum (FCS) to the solution and the single cell suspension was then followed by DMEM (D7777, Sigma-Aldrich) medium (44 mm NaHCO ₃ and 10 ml /) containing 10% FCS. Obtained by mechanical dissociation present in crushing cells in L) antibacterial / antifungal solution supplementation). Cells Depending on the application, were seeded in 96,12 or 6-well culture plates which are poly -D- lysine coated at an average density of 6 × 10 ⁴ cells / cm ^2, at _{37 ℃, 5% CO 2/} 95 Incubated in a humidified atmosphere containing% air. The culture medium was updated twice a week. Cells were stimulated and harvested between DIV14 and DIV17 when confluence and cell proliferation were optimal.

2.1 High-throughput screening for lactate secretion (HTS)
Lactic acid secretion was indirectly measured by acidification of extracellular medium by the high-throughput screening (HTS) method. For this purpose, primary astrocytes grown on 96-well plates for 17 days were stimulated with the compounds listed herein.

After washing the cells twice at 37 ° C. with stimulating medium (DMEM (D5030, Sigma), 3 mM NaHCO ₃ and 5 mM glucose), the cells are 10 μM extracellular pH sensor SNARF-5F 5- (and -6) -carboxylic acid. (Life Technologies Corporation) was stimulated with 10 μM (1% DMSO final) final concentration of compound in 50 μl of stimulating medium per well supplemented. Each compound was tested in duplicate on two different plates.

After 90 minutes of stimulation, fluorescence was exc. (Excitation) 480 nm / emm. (Emission) 580 nm and exc. 480 nm / emm. It was read at 630 nm. The fluorescence ratio between the luminescence value at 630 nm and the luminescence value at 580 nm, which represents the extracellular pH, was calculated.

In each plate, 8 wells were used for the negative control (DMSO) and 8 wells were used for the positive control (CCCP, 2 μM in DMSO). Z-prime values were calculated for each test plate and values <0 were truncated.

Calculate the mean and SD of the compound values tested in duplicate, and if the difference between the mean of the compound and the mean of the negative control exceeds 3 times the sum of the SD of the compound and the SD of the negative control, the compound is called HIT. Described. For the CDC54K library, only scores above 40% were considered lead hits, and for the remaining libraries all hits were considered. Scores are calculated as% of activity compared to positive controls (100%) on each plate.

After discarding these compounds, which are fluorescent (exc. 480 nm / emm. 580 nm or 630 nm) prior to irritation, primary screening hits were picked up on a new plate and confirmed for SNARF5 action. The extracellular medium was then analyzed to analyze the quantification of extracellular lactate for secondary screening.

2.2 Quantification of extracellular lactate The extracellular lactate of astrocytes seeded in 96 wells after 90 minutes of stimulation with the target drug (37 ° C, 5% CO ₂ /95% air condition). Determined in medium. The stimulus medium consisted of D5030 medium (filled with 5 mM D-glucose and 44 mM sodium bicarbonate) for 90 minutes at a concentration in the range of 0-100 μM.

Briefly, 200 μl of 0.2 M glycine (Sigma) -semicarbazide (Acros) pH 10 buffer containing 3 mM NAD (Roche) and LDH 14 U / ml (Roche) was supplemented with 20 μl of fresh D5030 complete medium. It was added to each well of a 96-well plate containing 30 μl of aliquot. Samples were incubated at 37 ° C. for 1 hour. After cooling the sample at room temperature, the fluorescence intensity (340 nm excitation / 450 nm emission) representing the amount of NADH produced was measured, and the lactic acid concentration value was determined from the standard curve of L-lactic acid.

2.3 Quantification of intracellular glycogen For glycogen administration, protein administration was performed first, and each replica was compared, and astrocytes collected from the primary cell culture produced sufficient and equivalent amounts of protein. We evaluated whether or not, and ensured that the difference obtained by glycogen quantification was due to the medicinal effect, not the amount of internal protein.

The astrocytes used in these medications were pre-grown in 6-well plates for 17 days and vehicle (DMSO) or the drug of interest (1 μM-100 μM) in _{5% CO 2/95% air at 37 ° C. in D5030 complete medium.} ) Was stimulated for 180 minutes. The medium was removed, replaced with 600 μl of 30 mM Tris HCl and stored at −20 ° C.

The protein was administered using the Micro BCA Protein Assay Kit (Thermo Scientific) as described in the manufacturer's instructions. Briefly, sonicated thawed cells, placed 5μl aliquots in clear 96 well plate, to which 30mM Tris-HCl, BCA mixture of 70μl of _{H 2} O and 100μl of 25 [mu] l (according to manufacturer's guidelines Manufactured to be) was added. After 120 minutes of incubation at 37 ° C., the absorbance was measured at a wavelength of 562 nm using a Safire2 spectrophotometer and the protein content was determined from the standard curve of bovine serum albumin (BSA).

Glycogen was quantified using 250 μl aliquots of similarly stimulated, thawed and sonicated cells. After a 30 minute incubation period at 90 ° C. and 400 rpm, 28 μl of 0.1 M sodium acetate / sodium acetate (both from Sigma) pH 4.6 buffer was added to each aliquot, which was then separated into two. Either placed each separation aliquot 5μl of amyloglucosidase (Roche) or 5μl of _{H 2} 0, it was incubated for 120 minutes in all cell solution vibration water bath at 37 ° C.. After centrifugation at 16000 G for 5 minutes, 20 μl of the supernatant was placed in a 96-well plate into which 0.67 mM ATP (Roche), 0.67 mM NADP (Roche), 1.8% hexokinase / glucose-6-phosphate. A mixture of 150 μl containing dehydrogenase (Roche) and 0.1 M Tris buffer HCl / 3.3 mM magnesium (Fluca) / pH 8.1 buffer was added. Fluorescence was measured using a Safari2 spectrophotometer (340 nm excitation / 440 nm emission). Glycogen concentration was obtained by subtracting the glucose value of the sample containing amyloglycosidase with respect to the sample not containing amyloglycosidase, and this was shown in comparison with a predetermined amount of protein.

2.4 MTT Survival Assay Astrocytes in 96-well plates were stimulated with test compounds in a gradient range of 0.1-200 μM for 24 hours (37 ° C., 5% CO ₂ /95%) to determine cytotoxicity. air). After stimulation, 5 mg / ml thiazole blue tetrazolium bromide (MTT, Sigma-Aldrich) in warm D5030 complete medium was added to each well and the cells were _{incubated at 37 ° C. (5% CO 2} ) for 4 hours. The medium was then removed by suction and the reaction was stopped by adding 50 μl DMSO per well.

The amount of reduced MTT (formazan) solubilized in DMSO was then spectroscopically determined using absorbance at 570 nm (Safire2; Tecan).

2.5 Production of Reactive Oxygen Species (ROS) Hydrogen peroxide (H ₂ O ₂ ) released into the supernatant is enzymatically detected with Amplex Red (Zhou, Diwoo et al., 1997). The oxidation of Amplex Red, is catalyzed by horseradish peroxidase in the presence of H ₂ O ₂ to highly fluorescent resorufin. The fluorescence scale is read with 545 nm excitation and 590 nm emission. The amount of H ₂ O ₂ is shown in comparison with the protein content extracted from cultured cells.

3. 3. In vivo Test 3.1 Mice Adult male or female C57B1 / 6J mice weighing 18-28 g (8 weeks old) were used for in vivo acute toxicity, in vivo chronic toxicity, pharmacodynamic and pharmacokinetic experiments (Charles River). Or Harlan).

Regarding the ALS mouse model, B6. G93A SOD1 transgenic male or female mice with SJL1-Gur / J genetic background were used (Jackson Laboratory).

All experiments were performed in strict accordance with the Guide to the Care and Use of Laboratory Animals (National Research Council 2011), which was approved by the relevant animal testing authorities.

Wires in a temperature (22 ± 2 ° C.) and humidity (55 ± 15%) controlled environment with a 12-hour light cycle (07.0 to 19.00 hours of lighting), except after surgery when the animals were individually housed. Animals were housed in groups of 3-5 in polypropylene cages (30 x 40 x 15 cm) with a mesh top.

3.2 In vivo drug administration An aqueous solution of the drug supplemented with 0.4% hydroxypropylmethylcellulose (HPMC) metocell 4KM (w / v) and 0.25% Tween-20 (v / v) as described above. Orally administered in (tube feeding). The compound was administered at 10 mg / kg. The concentration of the test drug was in the range of 10-100 mg / kg.

3.3 In vivo acute toxicity In vivo acute toxicity was evaluated at a maximum starting concentration of 100 mg / kg. If a toxic effect was observed at any time, the dose of the compound of the invention optimal for in vivo testing was obtained, such as by testing a second 10-fold lower concentration until a non-toxic concentration was reached. A group of 6-8 female mice was monitored for 14 days after a single oral dose of the drug, weighed daily and macroscopic histological examination was performed at the end of the experiment. Clinical assessments included observations of the mouse's ability to feed and water, notification of any visible pain, abnormal hair-growth or respiration, blood loss, evidence of microbial infection, and / or significant weight loss.

3.4 In vivo Chronic Toxicity Chronic toxicity was evaluated over 28 days in a group of 10 male and 10 female C57BL / 6J mice. The drug or vehicle was orally administered once daily as described above. During this period, clinical symptoms and body weight were recorded. At the end of 28 days, 3 mice per group were sacrificed for histopathological analysis. Other mice were left untreated for an additional 14 days, evaluated for delayed toxic effects, and then the same analysis was performed. Histopathological diagnosis was performed by a special platform of the mouse pathology facility at CHUV Hospital (Lausanne, Switzerland).

3.5 In vivo Pharmacodynamics-Lactate Biosensors Extracellular lactate levels were monitored in vivo using a Lactate biosensor (Pinnacle Technology) according to the manufacturer's instructions. Cannula, 5-7 days prior to compound administration, mouse brain motor cortex region M1 / M2 (coordinates: +1.94 mm (bregma), lateral-1.4 mm (midline), ventral-1.0 mm (Dura)) was surgically implanted. The drug was orally administered as described above and brain extracellular lactate levels were dynamically recorded for 6 hours. Mice were first administered vehicle alone and then 3 hours later vehicle or drug (10 or 100 mg / kg). The area under the curve (AUC) for quantifying fluctuations in extracellular lactate concentration for each test compound was calculated using Graphad Prism, and the ratio of AUC after drug-to-vehicle administration was calculated. A group of 8 male mice was used for each condition.

3.6 In vivo Pharmacodynamics-Quantitative Glycogen To measure intracerebral glycogen levels, mice are focused directly on the mouse brain using a microwave beam (1 second, 6 kW) at different time points after drug administration. Euthanized. This immobilization method results in a rapid inhibition of the enzymatic response, thereby keeping the metabolic state in the brain of the euthanized animal intact. Glycogen concentrations were quantified using standard biochemical procedures. A group of 8 male mice was used for each condition.

3.7 In vivo Pharmacokinetics 3.7.1 Surgical Mice were anesthetized with isoflurane (2% and 800 mL / min O _2). Preoperatively, finadyne (1 mg / kg, subcutaneous) was administered for analgesia during the intraoperative and postoperative recovery period. A mixture of bupivacaine and epinephrine was used for local anesthesia at the periosteal incision site of the skull.

3.7.2 Implantation of microdialysis probe in the prefrontal cortex (PFC) Animals were placed in stereotactic fixed frames (Kopf instruments, USA). A MetaQuant microdialysis probe (MQ-PAN3 / 3, Brainlink, Netherlands) with a 3 mm exposed polyacrylonitrile membrane was implanted in the prefrontal cortex (probe tip coordinates: AP = + 2.0 mm (bregma), lateral = −0. 7 mm (midline), ventral = -3.3 mm (dura), 0.0 mm and incisor rod set at an angle of 8 °). All coordinates were based on "The mouse brain in stereotactic coordinates" by Parxions and Franklin (2004). The probe was attached to the skull with a stainless steel screw and dental cement (Fuji Plus Capsules, Henry Chain, The Netherlands).

3.7.3 Transvenous cannula insertion Following the same surgical procedure, a catheter was placed intravenously to accommodate blood sampling. An indwelling cannula was inserted into the right transvenous and externalized by an incision in the upper part of the skull. The ends of the intravenous catheter were fixed in place with dental acrylic cement and attached to the skull with two stainless steel screws.

3.7.4 Experimental design The experiment was started one day after surgery. The MetaQuant microdialysis probe was connected to a microperfusion pump (CMA Microdialysis) with a flexible PEEK tube (Western Analytical Products Inc. USA; PK005-020) and perfused with CSF + 0.2% BSA at a flow rate of 0.12 μL / min. Ultrapure water + 0.2% BSA was used as a carrier stream at a flow rate of 0.80 μL / min. After a minimum of 1.5 hours of pre-stabilization, microdialysis samples were collected at 30 minute intervals. Samples were collected in polystyrene microvials (Microbiotech / se AB, Sweden; 4001029) using an automatic fraction collector (UV8301501, TSE, Univentor, Malta). After recovery of the three basal samples at t = 0 minutes, the drug of interest was orally administered. Eight additional samples were collected after administration of the compound. All samples were stored at -80 ° C until offline analysis.

In parallel, blood samples (50 μL) were taken intravenously via a cannula. These samples were collected at specified intervals in vials containing 5 μL of heparin (500 IE / mL in saline). The samples were mixed by inverting the tubes and then centrifuged at 4000 rpm (1500 × g) at 4 ° C. for 10 minutes. The supernatant was stored as plasma in 1.5 mL Eppendorf vials (Sarthtedt, Germany) at -80 ° C until offline analysis.

At the end of the experiment, animals were euthanized and tissue of the terminal brain was collected for visual histological verification of probe location.

3.8 Therapeutic effect-SOD1 G93A mouse model The ALS mouse model overexpresses the human mutant gene G93A SOD1. It is characterized by transgenic mice with an SJL1-Gur / J genetic background. The mating colonies are all B6. It consisted of a wild-type female mouse with an SJL1-Gur / J background and a male SOD1 G93A mouse. F1 pups were genotyped after ear punching at weaning using quantitative PCR (qPCR), which allows determination of SOD1 copy number in transgenic mice.

To test the therapeutic effect, SOD1 mice were administered the molecule of interest (10-100 mg / kg) or vehicle daily from 30 days after birth throughout life. Three groups were compared: wild-type mice treated with vehicle, G93A SOD1 mice treated with vehicle, and G93A SOD1 mice treated with the drug of interest. A group of at least 12 male and female mice was used. Body weight was recorded daily for each mouse throughout the procedure and neuromuscular function was measured once a week. Evaluation of neuromuscular function lies in the test of muscle strength using a grip strength test and the evaluation of the development of motor impairment on a score sheet by specific visual observation: normal gait (0), tail suspension, one leg contraction (1), When the tail is suspended, both legs are contracted (2), when walking, the legs are paralyzed (3), and when the mouse is placed on its back, it cannot return (4).

The 3.8.1 grip strength test experiment was performed in a room with a low light intensity of about 30 lux to avoid any additional stressful conditions. Mice were individually placed in the center of an elevated (35 cm high) upside-down 42 x 42 cm grid placed on a table lined with bubble sheets for up to 5 minutes. Muscle strength was evaluated by measuring the ability of mice to grip the grid (hours [seconds]).

3.8.2 Surviving mice were sacrificed when at least one of the predefined criteria was reached: i) loss of ≥15% of maximum mouse body weight, ii) ≥ by return when placed on the back It takes 20 seconds (4 criteria on the paralysis rating scale). The obtained Kaplan-Meier survival curve was then followed by Graphpad prism V.I. 6 was used for comparison.

4. Statistical analysis Statistical analysis is performed using independent or paired two-way student's t-test for pair comparison, or one-way or two-way ANOVA where appropriate for multiple pair comparison, followed by Dunnett, Bonferroni or Tukey HSD post-test. Prism v. I went at 6.

Summary of results 1. High-Throughput Cell Screening Identification of lactate enhancers by high-throughput screening (HTS) experiments of astrocyte primary cultures with 90 minutes extracellular pH dye (SNARF5F 5- (and 6-) carboxylic acid). Procedures are described in Materials and Methods (2. Cell Culture, 2.1 Lactate Secretory HTS and 2.2 Quantification of Extracellular Lactate).

The procedure was as follows:
-Primary screening: Acidification of extracellular medium-Confirmation of primary screening: Acidification of extracellular medium, exc. 480 nm / emm. Removal of compounds having fluorescent activity at 580 nm or 630 nm-Secondary screening: Dosing of extracellular lactate.

The first library screened was the Prestwick library consisting of 1240 FDA approved drugs (available from Prestwick Holding and Chemical Inc., USA). The optimal lactate release stimulant was found to be the following 19 hits in Table 1.

The next library tested was a CDC54K library consisting of 54,000 compounds (from EPFL, Lausanne, Swiss bioscreening facility) classified in the chemical family. Appendix I features a list of chemical motifs based on a structural analysis of the entire list of hits. Appendix II, which has been shown to be active, features a list of molecules that may be an addition to the molecules of Appendix I. The molecules listed in Table 1 and Appendix II above are referred to herein as "molecules of the invention".

Any molecule characterized by a motif, or any molecule associated with the molecular structure described in Appendix I and having suitable metabolic activity in at least one of the assays described herein, is also described herein in the book. It can be called the "molecule of invention".

2. 2. The in vitro characterization hit, lactate secretion (EC50), _{glycogenolysis,} (to avoid a molecule that stimulates glycolysis by blocking mitochondrial respiration) H 2 _{O 2} generation, and for their effects on cytotoxicity (LD50) , In vitro characterization in primary astrosite culture. Molecules were also characterized for their "dragability" by Pfizer's Rule of Five and the theoretical crossing of the blood-brain barrier (polar surface area <90 Å).

The technical procedure is described in Materials and Methods (2. Cell Culture).

a. Hits from the Prestwick library i. Lactate level Lactate levels secreted from astrocytes were measured in extracellular medium 90 minutes after stimulation with 20 hits (molecules) (10 μM each) from the Prestwick library, as shown in FIG. 1. = 6-10. The positive control is CCCP (2 μM). Statistical analysis resided in ANOVA, followed by Fisher LSD post-test for pair comparison. In addition, EC50s were calculated using a wide range of concentrations of Prestwick compounds (0-100 μM), as shown in Table 1 below.

ii. Glycogenolysis Intracellular glycogen levels in astrocytes were measured 3 hours after stimulation with 20 hits (10 μM each) from the Prestwick library, as shown in FIG.
n = 6-10. The positive control is glutamate (0.5 mM). Statistical analysis resided in ANOVA, followed by Fisher LSD post-test for pair comparison.

iii. Cytotoxicity by MTT An MTT cell viability assay was performed on astrocytes exposed to Prestwick hits (concentrations ranging from 0 μM to 200 μM). An example of a lead molecule is shown in FIG. The cytotoxicity results are outlined in Table 2 below.

iv. Mitochondrial activity Mitochondrial respiration in astrocytes was measured by _{H 2} O ₂ production 90 minutes after stimulation with Prestwick hits (10 μM each). FIG. 4 shows average absorbance + SEM; n = 4. CCCP (2 μM) was used as a positive control.

v. List Summary Table 2 shows the HTS score, the action of lactic acid (EC50), and the statistical significance of glycogenolysis (* p <0.05, ** p <0.01, *** p <0.001, **. ** p <0.0001), cytotoxicity measured by MTT (IC50), Pfizer's Rule of Five and total polar surface area (PSA), including an overview of the activity of Prestwick hits.

b. Hits from the CDC54K library i. Lactate level Lactate levels secreted from astrocytes were measured in extracellular medium 90 minutes after stimulation with hits (molecules) from the CDC54K library. EC50s were calculated using concentrations in the range 0-100 μM, as shown in Table 3 below. Lead hits from the CDC54K library tested were in one member of each 18CDC54K family. The results are shown in FIG. 5A.

ii. Glycogenolysis Figure 5B shows intracellular glycogen levels in astrocytes measured 3 hours after stimulation with 18 hits (10 μM each) from the CDC54K library; n = 6-10. Positive controls are glutamate or norepinephrine. Statistical analysis lies in ANOVA, followed by Fisher LSD post-test for pair comparison.

iii. Cytotoxicity by MTT An MTT cell viability assay was performed on astrocytes exposed to CDC 54K hits (concentrations in the range 0 μM to 200 μM). The IC50 data are outlined in Table 3.

iv. Mitochondrial activity Mitochondrial respiration in astrocytes was measured by _{H 2} O ₂ production 90 minutes after stimulation with CDC 54K hits (range 0-200 μM). The IC50 data are outlined in Table 3.

v. Listing Summary Table 3, HTS scores, the action of lactic acid (EC50), statistical significance of glycogenolysis, cytotoxicity _(IC50) as measured by _MTT, effects on H 2 _{O 2,} Pfizer rules of 5 and total polar An overview of the activity of CDC54K hits, including surface area (PSA), is shown.

3. 3. In vivo characterization a. Acute Toxicity In vitro-derived lead molecules were tested in vivo starting with acute toxicity / dose optimization in wild-type C57B1 / 6 female mice 14 days after dosing. During this period, mice were weighed and clinically monitored (feeding, watering, pain, grooming, respiration, blood loss, microbial infection). At the end of the 14-day evaluation, mice were sacrificed and high-level organ analysis was performed. The drug was always orally administered in a solution consisting of Metocell 4KM 0.4%, Tween 0.25% (tube feeding). The results are shown in FIG.

Overview-GP-03 was toxic at 100 mg / kg but not at 10 mg / kg (dose optimization).
-All other tested molecules (GP-01 to GP-07; GP-A, I, P, Q, R, V) were 100 mg / kg and were not toxic.

b. Chronic toxicity Chronic toxicity was evaluated prior to chronic administration in SOD1 mice. GP-01, 02, 04, 05, 06 and 07 were used at 10 mg / kg for C57B1 / 6 male and female mice. GP-03 was not tested because it was already toxic after acute administration of 100 mg / kg and did not show good PD effects at 10 mg / kg (see below for more information).

Mice were treated for 28 days, monitored for body weight and clinical symptoms, and then tested for anxiety in an elevated cross maze (EPM). Half of the mice were then slaughtered and pathologically analyzed into numerous organs (brain, tongue, esophagus, diaphragm, stomach, small intestine, pancreas, large intestine, kidney, adrenal gland, liver, spleen, pancreas, mesenteric lymph nodes, (Spleen, bone marrow, muscle), while half of the mice were sacrificed after 14 days to assess recovery and / or distant toxicity and perform the same pathological analysis. The results are shown in FIGS. 7 and 8.

Summary • Chronic administration of GP-06 at 10 mg / kg was toxic and was discontinued when weight loss was> 20%. Therefore, chronic administration of GP-06 at 10 mg / kg is not used in the chronic treatment of SOD1 mice.
GP-01, GP-02, GP-04, GP-05 and GP-07 are safe when administered chronically at 10 mg / kg.
EPM analysis showed that GP-06 treated mice had increased anxiety at the end of treatment, which correlates with the toxicity of chronic treatment. None of the other chronic treatments led to a significant increase in anxiety.
Pathological analysis performed at the CHUV mouse pathology facility was associated with minor treatments in GP-07-treated mice, including leukocyte cell infiltration, single cell necrosis in the liver, and bile duct proliferation. Showed the effect of The above also applies to localized, amorphous intraductal vacuoles in the kidney of one male mouse treated with GP-07.

c. Pharmacodynamics-Lactate Biosensors Post-drug administration by using lactate biosensors implanted in the cortex of free-moving mice to measure lactate levels in vivo to measure the biological effects of lead molecules in the brain. Quantified. The results are shown in FIG.

Overview GP-04, GP-05, GP-06 and GP-07 (Prestwick library) at 10 mg / kg and Family GP-I3, GP-P1 and GP-R1 at 100 mg / kg (10 mg / kg not yet) Test; CDC54K library) significantly increased brain lactate.

d. Pharmacodynamics-Glycogen Levels Glycogen levels were measured in the microwave-fixed mouse prefrontal cortex (PFC) (PFC, 6 kW, 1 second) to ensure enzyme inhibition and block glycogenolysis. Samples were then flash frozen prior to dosing.

First, glycogen levels were analyzed 1 hour, 3 hours and 6 hours after drug administration. The largest reduction in PFC glycogen was observed at 3 hours. This point was then used in dose-response experiments. Glycogen levels were quantified 3 hours after administration of GP-01-GP-07 at 1, 10 or 100 mg / kg. The results are shown in FIG.

Summary All molecules tested showed a significant reduction in brain glycogen levels at 10 mg / kg and / or 100 mg / kg, with the exception of GP-03.

e. Pharmacokinetics (PK)
PK was measured by CRO Brainsonline for GP-04, GP-05, GP-07, GP-R1 and GP-P1 in the prefrontal cortex and plasma of wild-type C56B1 / 6 mice. The results are shown in FIGS. 11A and 11B.

Overview • GP-04, GP-05, GP-07 and GP-R1 levels are in the therapeutic range (100 nM-1 μM) and are maintained for several hours in the post-tube feeding prefrontal cortex at 100 mg / kg.
GP-01, GP-02 and GP-P1 require chemical improvement to reach the goal with therapeutic doses in the brain.

4. SOD1 Mouse Model of ALS SOD1 G93A mice were used to test the neuroprotective effects of lactate enhancers in ALS. The drug was administered daily from P30 to the final stage. Body weight and neurological scoring (0-4) were recorded daily and muscle strength (grip strength test) and coordination (rotor rod) were tested weekly. The results are shown in FIG. The result of GP-07 alone is shown in FIG. 13, and the result of GP-04 alone is shown in FIG.

Summary • Treatment with GP-07 at 10 mg / kg significantly improved motor function (grip strength test), neurological scoring and survival of SOD1 male mice. No effect of GP-07 was observed in female SOD1 mice.
Treatment with GP-07 at 100 mg / kg (SOD1 male mouse) was significantly better at 10 mg / kg until week 14, became toxic at week 14, and accelerated animal mortality.
Treatment with GP-04 at 10 mg / kg improved motor function and neurological scoring up to P100 in both male and female SOD1 mice, but had no effect on survival. GP-04 seems to have an early onset effect rather than a late onset effect.
Treatment with GP-05 at 10 mg / kg did not affect motor function, neurological scoring or survival.

It will be appreciated that the various features of the invention described in relation to another embodiment for clarity can be provided in combination with a single embodiment. Conversely, the various features of the invention described in relation to a single embodiment for brevity can also be provided separately or in any suitable partial combination. Those skilled in the art will recognize that the present invention is not limited to those specifically shown and described herein. The scope of the present invention is defined only by the subsequent claims.

Claims (21)

A molecule selected from the group consisting of families A, C, E, F (7), F (6), G, I, M, PQRV and Y.
Family G

(In the formula, for family G, R is H, ethyl or methyl, and each of R1 to R4 is independently H, halogen, alkyl, or alkoxy).
Including
Family A

(In the formula, if R1 is H or an unsubstituted or nitrogen-substituted benzyl, R2 is H or alkyl, but R2 is H, then R1 is

not,
Further, however, the structure is not that of the catalog ID numbers F228-0365, F228-0351, F228-0856 or F228-0541 of Appendix I).
Including
Family C

(In the formula, R1 and R2 are H or methoxy, respectively, each of R3, R4 and R5 is independently alkyl, preferably ethyl, or H, preferably only one of R3 to R5 is alkyl, preferably. Ethyl, more preferably R4 is alkyl, most preferably ethyl,
However, the structure is not that of the catalog ID numbers T546472, F1462-0491, T5463709 or 4052-4279 of Appendix I).
Including
Family E

(In the formula, R is pentyl, benzyl, alkylbenzyl or R1, R2 is alkyl, cyclopentyl or cyclobutane, and R1 is.

Or

And
However, the structure is not that of the catalog ID number L287-1577 or L287-1758 of Appendix I).
Including
Family F (7)

(In the formula, R is alkyl, halogen, or alkoxy,
Each of R1 to R5 is independently H, alkyl, or alkoxy,
However, the structure is the catalog ID numbers K404-0672, K404-0183, K404-0796, F0524-0511, F0524-0507, F0522-0533, F0524-0488, K404-0400, T0507-8442, K404-0906, K404 in Appendix I. Not from -0842, K404-0852, K404-0914, K404-0915, K404-0828, K404-0863 or K404-0277)
Including
Family F (6)

(In the formula, for family F (6), R is H, halogen, alkyl or alkoxy,
R1, R2, R3 and R4 are each independently H, alkyl, or alkoxy, where if R1 is alkoxy, then R is not alkyl, preferably halogen or alkoxy.
However, the structure is the catalog ID numbers K404-0672, K404-0183, K404-0796, F0524-0511, F0524-0507, F0522-0533, F0524-0488, K404-0400, T0507-8442, K404-0906, K404 in Appendix I. Not from -0842, K404-0852, K404-0914, K404-0915, K404-0828, K404-0863 or K404-0277)
Including
Family I

(In the ceremony, for Family I, R is

, Or

And
For Family I, R1 is an unsubstituted or S, O or N substituted cyclopentadiene or benzene and R2 is an H or carbonyl.
For Family I, R1 is (alternative atoms at each position are shown in square brackets)

Selected from the group consisting of
Each of R3, R4 and R5 is independently H, alkyl (preferably methyl), and

And
However, the structure is the catalog ID numbers T636-2007, T636-1250, T636-2391, T636-0054, T636-0027, T636-1243, T636-2360, T636-0985, T636-0181, D278-0514, T636 in Appendix I. Not from -1715, T636-2144, T636-1601 or T636-0973)
Including
Family M

(In the formula, R is H or alkyl, where R is unsubstituted or halogen (preferably F or Cl, more preferably F, preferably up to 3 halogens) substituted methyl or ethyl. It is preferably ethyl, but the structure is not that of Appendix I catalog ID number T543365).
Including
Family PQRV (square brackets indicate that the atom at that position may be C or N),

(In the formula, R1 is benzyl

Or

And
R2 is alkyl, forming or absent heterocyclic hexyl moieties with the nitrogen to which it is attached.
Each of R3, R4, R5 and R6 is halogen, H, alkyl, benzyl or alkylbenzyl (unsubstituted or nitrogen-substituted), cyclopentadiene or alkylcyclopentadiene (S or N-substituted or unsubstituted) or carbamoyl (optionally). (Alkylated with cyclopropane), R4 and R5 may be S and / or N-substituted or unsubstituted, and optionally alkylated cyclopentadiene together.
R7 to R11 are each independently halogen, alkyl, or methoxy and may be the same or different, or pyrrolidine, optionally formylpyrrolidine, in which case R7 is preferably pyrrolidine.
However, the structure is not that of the catalog ID numbers P025-0462, P025-0080, P025-0168, T5581430, F0376-0203, or T5246417 of Appendix I.
However, R1

If, R2 forms a heterocyclic hexyl moiety with the nitrogen to which it is attached,
However, R1

If R7 is pyrrolidine and [C, N] is C, then R4 is not a cyclopentadiene or alkylcyclopentadiene substituted with both S and N.
However, R1

If [C, N] is N and R3 to R6 are H, then none of R7 to R11 is methyl, methoxy or halogen.
However, R1

If, any of R7 to R11 is chlorine and [C, N] is N, in which case R5 is not carbamoyl.
However, R1

If, [C, N] is C, any of R7 to R11 is halogen or methoxy, and R4 and R5 together form an S and / or N-substituted cyclopentadiene, in which case cyclopentadiene. The pentadiene moiety is not alkylated and is not characterized by a benzyl group)
Including
Family Y

(In the formula, R is alkyl, S or halogen, preferably S or halogen, in the case of halogen, preferably F, in the case of S, preferably methylthio or ethylthio, most preferably methylthio.
However, the structure is not that of the catalog ID number L995-0405 or L995-0386 in Appendix I)
The molecule comprising. For family G, R is methyl or ethyl, for R1 to R4, for halogen, one or more of R1 to R4 is F or Cl, and for alkyl, one or more is ethyl or methyl. , In the case of alkoxy, one or more are ethoxy or methoxy,
For family A, R1 is nitrogen-substituted benzyl or H and R2 is H.
For Family C, R1 and R2 are each methoxy, and each of R3 to R5 is ethyl in the case of alkyl.
For family E, if R is pentyl or R1 and R2 is alkyl, then R2 is methyl or ethyl and
For family F (6), if R is halogen, R is F or Cl, R is alkyl, R is methyl or ethyl, R is alkoxy, then R is methoxy or ethoxy. Yes,
If any of R1 to R5 is alkyl, then it is methyl, if any of R1 to R5 is alkoxy, then it is methoxy or ethoxy, but if R1 is alkoxy, then R is Not alkyl and preferably halogen or alkoxy,
For family F (7), if R is alkyl, R is ethyl or methyl, R is halogen, R is Cl or F, and R is alkoxy, then R is methoxy or ethoxy. If any of R1 to R5 is alkyl, then it is methyl, and if any of R1 to R5 is alkoxy, then it is methoxy or ethoxy,
For family M, where R is alkyl, then R is unsubstituted or halogen-substituted methyl or ethyl.
For family Y, if R is alkyl, then R is ethyl or methyl, if R is S, then R is methylthio or ethylthio, and if R is halogen, then R is F.
The molecule according to claim 1. For Family G, each of R1 to R4 is methyl if alkyl and methoxy if alkoxy.
For family C, only one of R3 to R5 is ethyl and the rest is H.
For family M, if R is alkyl, then R is ethyl and
For family Y, R is S or halogen,
The molecule according to any one of the above claims. For Family G, at least two of R1 to R4 are halogens, at least two are alkyls, one is alkoxy and one is alkyl, one is alkyl and one is H, and one is halogen and 1 One is H, or one is alkoxy and one is H,
For family C, R4 is ethyl and R3 and R5 are H.
For family M, where R is ethyl, R is substituted with F or Cl, more preferably F, preferably up to 3 halogens.
For family Y, if R is S, then R is methylthio,
The molecule according to any one of the above claims. For Family G, the molecule is selected from the group consisting of G1 to G6 in Appendix I (Molecules with Catalog Numbers L924-1031; L924-1088; L924-0830; L924-0760; L924-0884; or L924-0988). ,
For Family A, molecules are selected from the group consisting of A1 to A3 in Appendix I (molecules with catalog numbers F228-0422, F228-0350 or F228-0534).
For Family C, molecules are selected from the group consisting of C1 to C3 in Appendix I (molecules with catalog numbers T5463586, 4052-4304 or T546658).
For Family E, molecules are selected from the group consisting of E1 to E4 in Appendix I (molecules with catalog numbers L287-0468, L287-1641, L287-1221 and L287-0220).
For family F (6), the numerator is selected from the group consisting of F4 to F6, F8, F9, F13 of Appendix I (catalog numbers K404-0800, K404-0673, F0524-0338, K404-0685, K404-0697). And molecules with K404-0394),
For family F (7), the numerator is selected from the group consisting of F1-F3, F7, F10-F12 in Appendix I (catalog numbers K404-0834, K404-0838, K404-0885, K404-0910, K404-0855). , K404-0860 and F0524-0611),
For Family I, the molecule is selected from the group consisting of I1-I5 and I7 of Appendix I (Molecules with Catalog Numbers T636-1937, T636-1114, T636-2387, T636-0134, T636-1210 and T636-2425. ),
For Family M, molecules are selected from the group consisting of M1 and M2 in Appendix I (molecules with catalog numbers T5599014 and T5653029).
For family PQRV, the molecule is selected from the group consisting of P1, Q1-Q3, R1, V1 and V2 of Appendix I (molecules having catalog numbers P025-0159, T5644899, T5599698, T5618591, T5580243, T6937001 and T5511047). And for family Y, the molecule is selected from the group consisting of Y1 and Y2 in Appendix I (molecules with catalog numbers L995-0125 and L995-0058).
The molecule according to any one of the above claims. A pharmaceutical composition comprising the molecule according to any one of the above claims. The molecule or pharmaceutical composition according to any one of the above claims for use as a drug. The molecule or pharmaceutical composition of claim 7, wherein the neurological disorder comprises ALS (Amyotrophic Lateral Sclerosis), a subtype thereof or a related disorder, for the treatment of said neurological disorder. The molecule of the present invention according to any one of the above claims, or a pharmaceutical composition containing the above, which is a method for treating a mammal in need of the treatment and for treating a neurological disease. The method comprising administering to the mammal, wherein the neurological disorder comprises ALS (Amyotrophic Lateral Sclerosis), a subtype thereof or a related disorder. A molecule, or pharmaceutical composition comprising said, for the treatment of a neurological disorder, wherein the neurological disorder comprises ALS (Amyotrophic Lateral Sclerosis), a subtype thereof or a related disorder, wherein the molecule comprises.
A molecule of the invention selected from the group consisting of families A, C, E, F (7), F (6), G, I, M, PQRV and Y.
Family G

(In the formula, for family G, R is H, ethyl or methyl, and each of R1 to R4 is independently H, halogen, alkyl, or alkoxy).
Including
Family A

(In the formula, if R1 is H or an unsubstituted or nitrogen-substituted benzyl, R2 is H or alkyl, but R2 is H, then R1 is

not,
Further, however, the structure is not that of the catalog ID numbers F228-0365, F228-0351, F228-0856 or F228-0541 of Appendix I).
Including
Family C

(In the formula, R1 and R2 are H or methoxy, respectively, each of R3, R4 and R5 is independently alkyl, preferably ethyl, or H, preferably only one of R3 to R5 is alkyl, preferably. Ethyl, more preferably R4 is alkyl, most preferably ethyl,
However, the structure is not that of the catalog ID numbers T546472, F1462-0491, T5463709 or 4052-4279 of Appendix I).
Including
Family E

(In the formula, R is pentyl, benzyl, alkylbenzyl or R1, R2 is alkyl, cyclopentyl or cyclobutane, and R1 is.

Or

And
However, the structure is not that of the catalog ID number L287-1577 or L287-1758 of Appendix I).
Including
Family F (7)

(In the formula, R is alkyl, halogen, or alkoxy,
Each of R1 to R5 is independently H, alkyl, or alkoxy,
However, the structure is the catalog ID numbers K404-0672, K404-0183, K404-0796, F0524-0511, F0524-0507, F0522-0533, F0524-0488, K404-0400, T0507-8442, K404-0906, K404 in Appendix I. Not from -0842, K404-0852, K404-0914, K404-0915, K404-0828, K404-0863 or K404-0277)
Including
Family F (6)

(In the formula, for family F (6), R is H, halogen, alkyl or alkoxy,
R1, R2, R3 and R4 are each independently H, alkyl, or alkoxy, where if R1 is alkoxy, then R is not alkyl and preferably halogen or alkoxy.
However, the structure is the catalog ID numbers K404-0672, K404-0183, K404-0796, F0524-0511, F0524-0507, F0522-0533, F0524-0488, K404-0400, T0507-8442, K404-0906, K404 in Appendix I. Not from -0842, K404-0852, K404-0914, K404-0915, K404-0828, K404-0863 or K404-0277)
Including
Family I

(In the ceremony, for Family I, R is

Or

And
For Family I, R1 is an unsubstituted or S, O or N substituted cyclopentadiene or benzene and R2 is an H or carbonyl.
For Family I, R1 is (alternative atoms at each position are shown in square brackets)

Selected from the group consisting of
R3, R4 and R5 are independently H and alkyl (preferably methyl), respectively.

and

And
R6 preferably contains nitrogen as a cyano group and
However, the structure is the catalog ID numbers T636-2007, T636-1250, T636-2391, T636-0054, T636-0027, T636-1243, T636-2360, T636-0985, T636-0181, D278-0514, T636 in Appendix I. Not from -1715, T636-2144, T636-1601 or T636-0973)
Including
Family M

(In the formula, R is H or alkyl, where R is unsubstituted or halogen (preferably F or Cl, more preferably F, preferably up to 3 halogens) substituted methyl or ethyl. It is preferably ethyl, but the structure is not that of Appendix I catalog ID number T543365).
Including
Family PQRV (square brackets indicate that the atom at that position may be C or N),

(In the formula, R1 is benzyl,

Or

And
R2 is alkyl, forming or absent heterocyclic hexyl moieties with the nitrogen to which it is attached.
Each of R3, R4, R5 and R6 is halogen, H, alkyl, benzyl or alkylbenzyl (unsubstituted or nitrogen-substituted), cyclopentadiene or alkylcyclopentadiene (S or N-substituted or unsubstituted) or carbamoyl (optionally). , Cyclopropane alkylated), and R4 and R5 may be S and / or N-substituted or unsubstituted, and optionally alkylated cyclopentadiene together.
Each of R7 to R11 is independently a halogen, alkyl, or methoxy and may be the same or different, or pyrrolidine, optionally formylpyrrolidine, in which case R7 is preferably pyrrolidine.
However, the structure is not that of the catalog ID numbers P025-0462, P025-0080, P025-0168, T5581430, F0376-0203 or T5246417 of Appendix I).
Including
Family Y

(In the formula, R is alkyl, S or halogen, preferably S or halogen, in the case of halogen, preferably F, in the case of S, preferably methylthio or ethylthio, most preferably methylthio.
However, the structure is not that of the catalog ID number L995-0405 or L995-0386 in Appendix I)
With the molecule, including
A molecule of the invention selected from the group consisting of the molecules described in Appendix I, wherein the molecule is Catalog ID No. T0502-5560; T0508-5190, T202-1455, T202-0973, K851-0113, T563309, The molecule and the molecule selected from the group consisting of T5672380, T5967389, T588038, T5231424, T0517-8250, T0511-9200 and T5627721.
The molecules shown in Table 1 of the present specification and
The molecules described in Appendix II, the molecules of which are Catalog ID Nos. T601789, T5993799, T5813085, T6947848, T0517-4117, T5729557, T570552, Z606-8352, LI15-0403, T5712071, T5790476, T5788339, G433-0293 , T5719257, T5798761, T5821723, T5787526, T58277594, K405-2595, T5274959, M950-1515, T5450239, G508-0015, T5707230, T5710343, 887-0183, T5453923, T0505-4087, T5677323 -0128, T0500-6629, T5832764, M508-0370, T0515-1783, T5393500, T5672380, M381-0730, Z606-8287, G855-0143, Z076-0028, T5311200, E944-0182, L302-0069, T5770640, G869 -0064, T5753165, G855-0183, T53529723, T533260, L932-0267, L302-0181, T5444083, T6125251, T5694329, T0517-2783, T5788545, T5586091, T5967389, T5783794, T5494352, 037467 , T5318833, Z606-8351, T5606387, T0516-6894, T5691896, Z606-8298, F5285-0069, T993-1787, Z606-5341, F3394-1364, Y030-2832, T540234, T5389517, Z603-8037, T0513-02 , And the molecule or pharmaceutical composition selected from the group consisting of said molecules, selected from the group consisting of T636-2387. For family PQRV, R2 is alkyl, forming or absent heterocyclic hexyl moieties with the nitrogen to which it is attached.
Each of R3, R4, R5 and R6 is halogen, H, alkyl, benzyl or alkylbenzyl (unsubstituted or nitrogen-substituted), cyclopentadiene or alkylcyclopentadiene (S or N-substituted or unsubstituted) or carbamoyl (optionally). , Cyclopropane alkylated), and R4 and R5 together may be S and / or N-substituted, or unsubstituted, and optionally alkylated cyclopentadiene.
Each of R7 to R11 is independently halogen, alkyl, or methoxy and may be the same or different, or pyrrolidine, optionally formylpyrrolidine, in which case R7 is preferably pyrrolidine.
However, the structure is not that of the catalog ID numbers P025-0462, P025-0080, P025-0168, T5581430, F0376-0203 or T5246417 of Appendix I.
However, R1

If, R2 forms a heterocyclic hexyl moiety with the nitrogen to which it is attached,
However, R1

If R7 is pyrrolidine and [C, N] is C, then R4 is not a cyclopentadiene or alkylcyclopentadiene substituted with both S and N.
However, R1

If [C, N] is N and R3 to R6 are H, then none of R7 to R11 is methyl, methoxy or halogen.
However, R1

If any of R7 to R11 is chlorine and [C, N] is N, then R5 is not carbamoyl and
However, R1

If [C, N] is C, any of R7 to R11 is halogen or methoxy, and R4 and R5 together form an S and / or N-substituted cyclopentadiene, in which case cyclopentadiene. The moiety is not alkylated and it is not characterized by a benzyl group,
For Family I, R6 is absent,
The molecule according to claim 10 or a pharmaceutical composition containing the above. For family G, R is methyl or ethyl, for R1 to R4, for halogen, one or more of R1 to R4 is F or Cl, and for alkyl, one or more is ethyl or methyl. , In the case of alkoxy, one or more are ethoxy or methoxy,
For family A, R1 is nitrogen-substituted benzyl or H and R2 is H.
For Family C, R1 and R2 are each methoxy, and each of R3 to R5 is ethyl if alkyl.
For family E, if R is pentyl or R1 and R2 is alkyl, then R2 is methyl or ethyl and
For family F (6), if R is halogen, R is F or Cl, R is alkyl, R is methyl or ethyl, R is alkoxy, then R is methoxy or ethoxy. Yes,
If any of R1 to R5 is alkyl, then it is methyl, if any of R1 to R5 is alkoxy, then it is methoxy or ethoxy, but if R1 is alkoxy, then R is Not alkyl and preferably halogen or alkoxy,
For family F (7), if R is alkyl, R is ethyl or methyl, R is halogen, R is Cl or F, and R is alkoxy, then R is methoxy or ethoxy. Yes, if any of R1 to R5 is alkyl, then it is methyl, and if any of R1 to R5 is alkoxy, then it is methoxy or ethoxy, and
For family M, where R is alkyl, then R is unsubstituted or halogen-substituted, methyl or ethyl,
For family Y, if R is alkyl, then R is ethyl or methyl, if R is S, then R is methylthio or ethylthio, and if R is halogen, then R is F.
The molecule according to claim 10 or 11, or a pharmaceutical composition containing the above. For Family G, each of R1 to R4 is methyl if alkyl and methoxy if alkoxy.
For family C, any one of R3 to R5 is ethyl and the rest is H.
For family M, if R is alkyl, then R is ethyl and
For family Y, R is S or halogen,
The molecule according to any one of claims 10 to 12 or a pharmaceutical composition containing the above. For Family G, at least two of R1 to R4 are halogens, at least two are alkyls, one is alkoxy and one is alkyl, one is alkyl and one is H, and one is halogen and 1 One is H, or one is alkoxy and one is H,
For family C, R4 is ethyl and R3 and R5 are H.
For family M, where R is ethyl, R is substituted with F or Cl, more preferably F, preferably up to 3 halogens.
For family Y, if R is S, then R is methylthio,
The molecule according to any one of claims 10 to 13 or a pharmaceutical composition containing the above. For Family G, the molecule is selected from the group consisting of G1 to G6 in Appendix I (Molecules with Catalog Numbers L924-1031; L924-1088; L924-0830; L924-0760; L924-0884; or L924-0988). ,
For Family A, molecules are selected from the group consisting of A1 to A3 in Appendix I (molecules with catalog numbers F228-0422, F228-0350 or F228-0534).
For Family C, molecules are selected from the group consisting of C1 to C3 in Appendix I (molecules with catalog numbers T5463586, 4052-4304 or T546658).
For Family E, molecules are selected from the group consisting of E1 to E4 in Appendix I (molecules with catalog numbers L287-0468, L287-1641, L287-1221 and L287-0220).
For family F (6), the numerator is selected from the group consisting of F4 to F6, F8, F9, F13 of Appendix I (catalog numbers K404-0800, K404-0673, F0524-0338, K404-0685, K404-0697). And molecules with K404-0394),
For family F (7), the numerator is selected from the group consisting of F1-F3, F7, F10-F12 in Appendix I (catalog numbers K404-0834, K404-0838, K404-0885, K404-0910, K404-0855). , K404-0860 and F0524-0611),
For Family I, the molecule is selected from the group consisting of I1-I5 and I7 of Appendix I (Molecules with Catalog Numbers T636-1937, T636-1114, T636-2387, T636-0134, T636-1210 and T636-2425. ),
For Family M, molecules are selected from the group consisting of M1 and M2 in Appendix I (molecules with catalog numbers T5599014 and T5653029).
For family PQRV, the molecule is selected from the group consisting of P1, Q1-Q3, R1, V1 and V2 of Appendix I (molecules having catalog numbers P025-0159, T5644899, T5599698, T5618591, T5580243, T6937001 and T5511047). And for family Y, the molecule is selected from the group consisting of Y1 and Y2 in Appendix I (molecules with catalog numbers L995-0125 and L995-0058).
The molecule according to any one of claims 10 to 14 or a pharmaceutical composition containing the above. The molecule or pharmaceutical composition of the present invention according to any one of claims 10 to 15, which is a method for treating a mammal in need of the treatment and for treating a neurological disease. The method, wherein the neurological disorder comprises ALS (Amyotrophic Lateral Sclerosis), a subtype thereof or a related disorder. The molecule, pharmaceutical composition or method according to any one of the preceding claims, wherein the subtype comprises medulla oblongata onset ALS or limb onset ALS. The molecule, pharmaceutical composition or method according to any one of the preceding claims, wherein the related disease comprises one of primary lateral sclerosis (PLS), progressive medulla oblongata or progressive muscular atrophy. The molecule, pharmaceutical composition or method according to any one of the preceding claims, further comprising administering a drug selected from the group consisting of riluzole and edaravone. The molecule, pharmaceutical composition or method according to any one of the preceding claims, further comprising providing a non-drug treatment selected from the group consisting of invasive and non-invasive mechanical ventilation. The molecule, pharmaceutical composition or method according to any one of the claims, further comprising delaying the onset of the disease in an individual at risk of developing the disease according to one or more predictive markers.

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